Novel non-natural C-linked carbo-beta-peptides with robust secondary structures

ABSTRACT

This invention relates to Novel nonnatural C-linked carbo-β-peptides with robust secondary structures, which comprises the synthesis of a new class of β-peptides called C-linked carbo-β-peptides, most of which are favorably disposed for the formation of stable helical structures.  
                 
 
     n=0, 1, 2, 3 . . .  
     R=H, Boc, Cbz, Fmoc, acetyl or salts such as HCl, TFA and others  
     R 1 =—O alkyl, —O-aralkyl, -amine, alkylamine, aryalkyl maine  
     R 2 =R 3 =R 4 =R 5 =H  
     R 2 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 3 =R 4 =R 5 =H  
     R 3 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 2 =R 4 =R 5 =H  
     R 4 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 2 =R 3 =R 5 =H  
     R 5 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 2 =R 3 =R 4 =H  
     R 2 =R 4 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 3 =R 5 =H  
     R 3 =R 5 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 2 =R 4 =H  
     R 2 =R 5 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 3 =R 4 =H  
     R 3 =R 4 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 2 =R 5 =H  
     R 2 =R 3 =sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 4 =R 5 =H  
     R 4 =R 5  sugar or hydroxy alkyl, amino alkyl/thioalkyl, R 2 =R 3 =H  
     Sugars can be monosaccharide pentoses such as D-xylo, D-ribo, D-lyxo, D-ara or the L-sugars such as L-xyl, L-rib, L-lyxo, L-ara in furanoside or pyranoside form; hexoses such as D and L-glc, D and L-gal, D and L-man, D and L-gul, D and L-all, etc. in furanoside/pyranoside form; disaccharides such as lactose, maltose, cellobiose etc.; filly protected as acetates, benzoates, allyl or aralkyl ethers, alkylidene dioxolane derivatives, thio derivatives or totally unprotected sugars, D and L sugars in furanoside/pyranoside form having heterocyclic bases such as adenine, guanine, thymidine, cytosine or unnatural bases or heterocyclics having one or more than one heteroatoms such as O/N/S both in 5 and 6 membered rings, deoxy sugars/amino sugars natural/non-natural, rare sugars and higher sugars, bifunctional sugar amino acids.

FIELD OF THE INVENTION

[0001] The present invention relates to Novel nonnatural C-linkedcarbo-β-peptides with robust secondary structures and process for thepreparation of the said compounds.

[0002] The said novel β-peptides are derived from the coupling of avariety of C-linked carbohydrate β-amino acids. These β-peptides containa variety of carbohydrate moieties on the backbone of β-peptide ascarbohydrate recognition sites. The thus made β-peptides have shownstable helical structures.

BACKGROUND OF THE WORK

[0003] Reference may be made to J. Am. Chem. Soc., 116, 1054-1062(1994), by Gellman et al, wherein the β- and γ-amino acids werepostulated to fold in the same manner as α-amino acids throughintramolecular hydrogen bonding.

[0004] In 1996, two groups of scientists, one led by Seebach et al andanother by Gellman et al reported the first synthesis of β-peptidesshowing well-defined secondary structures. Reference may be made toHelv. Chim. Acta 79, 913-941 and 2043-2066 (1996), wherein it was thefist group worked on the synthesis of β-hexapeptide consisting ofacyclic β-amino acid monomers and explored for the secondary structuresalong with effects of residue variation on the secondary structures.

[0005] Reference may be made to J. Am. Chem. Soc., 118, 13071-72 (1996),wherein Gellman group worked on the synthesis of β-peptides containing acyclohexane 1,2-amino acid (ACHC) as β-amino acid monomer to derive a14-helical structure. Reference may further be made to Nature 387, 381(1997), wherein cyclopentane amino acid (ACPC) gave 12-helicalstructure.

[0006] Reference may be made to Helv. Chim. Acta 81, 932 (1998), whereinSeebach's group worked on β²-β³ mixed hexapeptide which exhibited a12/10/12 helix (10/12 helix). while reference may be made to Helv. Chim.Acta. 81, 2218-2243(1998), wherein β^(3,3), β^(2,2) amino acids andtheir β-peptides were prepared, while β^(3,3) have shown 8-helix

[0007] Reference may be made to Angew. Chem. Int. Ed , 41, 230-253(2002); Chem. Rev. 102, 491-514 (2002); Chem. Eur. J., 8, 4366-4376(2002), which reviewed about a new class of ‘sugar amino acids’ whereinboth the acid and amine components are installed on the carbohydrateframe and a variety of α, β, γ, δ, -sugar amino acids were prepared andconverted into the corresponding peptides of a variety of secondarystructures and biological activities.

OBJECTIVES OF THE INVENTION

[0008] The main object of the present invention is to synthesize a newclass of C-linked carbo β-peptides.

[0009] Other object is to synthesize a new class of β-amino acids havingcarbohydrate moieties as side chains.

[0010] Yet another object is to convert the thus made newer C-linkedcarbo β-amino acids into the corresponding C-linked carbo β-peptides asa new class of β-peptides.

[0011] A further object is to synthesise these new C-linked carboβ-peptides as proteolytically stable peptide molecules.

[0012] The other object to synthesise the new class of C-linked carboβ-peptides is to enhance the water solubility and stability.

[0013] The objective for the synthesis of these new C-linked carboβ-peptides is to enhance the carbohydrate recognition sites in thepeptides thus made.

[0014] Another object is to enhance the activity of the thus madepeptides for their biological profile and develop them into anti-cancer,anti-microbial and other therapeutic class agents.

[0015] Another object of the present invention provides novel processesfor the synthesis of said novel β-amino acids and β-peptides that wouldexhibit interesting biological activity. These synthetic process routesutilize commercial reagents and facilitate large scale preparation, andprovide the new class of C-lined carbo β-peptides in sufficientquantities for further biological evaluation,

[0016] Another object of the present invention is to use chirality asthe controlling point in giving stable secondary structures. C-Linkedcarbo β-amino acids, epimeric at the amine center for making theC-linked carbo β-peptides having stable secondary structures.

[0017] Other object of the present invention is to synthesize C-linkedβ-peptides with C-linked carbo β-amino acid with D configuration,C-linked β-amino acids with L-configuration and mixed peptides with Dand L-C-linked carbo-β-amino acids.

DESCRIPTION OF THE DRAWINGS

[0018]FIG. 1 represents the structure of poly β-alanine, wherein thehydrogen bonding is depicted indicating a variety of helical structurespossible.

[0019]FIG. 2 represents Circular Dichroism (CD) plot for 43 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0020]FIG. 3 represents Circular Dichroism (CD) plot for 38 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0021]FIG. 4 represents Circular Dichroism (CD) plot for 41 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0022]FIG. 5 represents Circular Dichroism (CD) plot for 42 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0023]FIG. 6 represents Circular Dichroism (CD) plot for 23 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0024]FIG. 7 represents Circular Dichroism (CD) plot for 26 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0025]FIG. 8 represents Circular Dichroism (CD) plot for 27 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

[0026]FIG. 9 represents Circular Dicbroism (CD) plot for 52 in MeOH andits simulated model, where sugar is replaced with methyl for clarity andclear visualization.

SUMMARY OF THIS INVENTION

[0027] Accordingly the present invention provides Novel nonnaturalC-linked carbo-β-peptides with robust secondary structures, whichcomprises of the synthesis of a new class of β-peptides called C-linkedcarbo-β-peptides, most of which are favorably disposed for the formationof stable helical structures.

[0028] In an embodiment of the present invention, it would be desirableto synthesize new class of β-peptides, since the β-amino acids are partstructures of several biologically active compounds.

[0029] In another embodiment of the present invention it deals with thesynthesis of C-linked carbo β-amino acids since several sugar aminoacids are part structures of biologically active compounds.

[0030] In yet another embodiment these new β-peptides, havingcarbohydrate moieties, would find immense use as biologically activecarbo-β-peptides, the rationale for the synthesis of such new class ofC-linked carbo β-peptides is to derive small bioactive peptides reportedin this invention are as below:

[0031] 1) β-peptides derived from β-amino acids unlike peptides fromα-amino acids are metabolically more stable, since they are non-natural.

[0032] 2) The β-peptides thus made in this invention due to the presenceof carbohydrate structures would act as recognition sites.

[0033] 3) The presence of carbohydrate moieties on the β-peptide chainwould enhance the solubilities of these peptides tremendously, therebyfacilitating the transportation.

[0034] 4) The β-peptides thus made from C-linked carbo β-amino acidswould impart a high degree of amphiphilicity due to the hydrophilicnature of the β-peptides.

[0035] 5) The β-peptides with C-linked carbo β-amino acids thus madewould show their peptide activity and can possess other favorablecharacters which are imparted such as enzymatic stability and transportprofiles.

[0036] 6) The β-peptides thus made from C-linked carbo β-amino acids dueto the presence of both the carbohydrate and peptide moieties in theirskeletons, would enhance the process of peptide based drug discovery,devoid of the problems associated with solubilities of peptide basedactive compounds. In addition, it imparts the proteolytic tolerance tothese compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention is related to the synthesis of C-linkedcarbo-β-peptides. Some of which favor the formation of novel helicalsecondary structures such as 12, 14 or 10/12 helices. The presence ofcarbohydrate moiety on the β-peptide backbone is desirable since, ithelps not only as sugar recognition center in the new β-peptides, butalso attributes amphiphilicity due to hydrophilic nature.

[0038] The synthetic protocol developed in the present invention issuitable for the synthesis of β-peptides with the following formula I.

[0039] n=0, 1, 2, 3 . . .

[0040] R=H, Boc, Cbz, Fmoc, acetyl or salts such as HCl, TFA and others

[0041] R¹=—O alkyl, —O-aralkyl, -amine, alkylamine, aryalkyl maine

[0042] R²=R³=R⁴=R⁵=H

[0043] R²=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R³=R⁴=R⁵=H

[0044] R³=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R⁴=R⁵=H

[0045] R⁴=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R³=R⁵=H

[0046] R⁵=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R³=R⁴=H

[0047] R²=R⁴=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R³=R⁵=H

[0048] R³=R⁵=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R⁴=H

[0049] R²=R⁵=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R³=R⁴=H

[0050] R³=R⁴=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R⁵=H

[0051] R²=R³=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R⁴=R⁵=H

[0052] R⁴=R⁵=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R³=H

[0053] Sugars can be monosaccharide pentoses such as D-xylo, D-ribo,D-lyxo, D-ara or the L-sugars such as L-xyl, L-rib, L-lyxo, L-ara infuranoside or pyranoside form; hexoses such as D-and L-glc, D-and L-gal,D-and L-man, D-and L-gul, D-and L-all, etc. in furanoside/pyranosideform; disaccharides such as lactose, maltose, cellobiose etc.; fullyprotected as acetates, benzoates, allyl or aralkyl ethers, alkylidenedioxolane derivatives, thio derivatives or totally unprotected sugars, Dand L sugars in furanoside/pyranoside form having heterocyclic basessuch as adenine, guanine, thymidine, cytosine or unnatural bases orheterocyclics having one or more than one heteroatoms such as O/N/S bothin 5 and 6 membered rings, dexoy sugars/amino sugarsnatural/non-natural, rare sugars and higher sugars, bifunctional sugaramino acids

[0054] The present invention provides a new class of C-linked carboβ-peptides having basic structure as depicted in structural formula I.

[0055] The main advantage of the present invention is that it allows theconstruction of C-linked carbo β-peptides hitherto unknown class, withsecondary structures of high stability, the formation of the proposedsecondary structures is well controlled through the variation ofchirality at the a e bearing carbon stereo centre of C-linked β-aminoacid monomer. Since these unnatural β-peptides can be synthesized withwell defined and stable secondary structures, they can mimic thesecondary structures of natural protein and thereby disrupt thebiological interactions of biopolymers (proteins). Since, these peptidesadopt stable secondary structures through chirality control, they arewell suited for molecular design. Further to the invention, the C-linkedcarbo β-peptides are useful as base molecules to synthesize an array ofpeptide libraries with varying the sequence of β-amino acid carbohydratemoieties, functional groups and the like. Since the chirality plays aprominent role in deriving the secondary structures altering thesubstituent accordingly do not substantially disturb the secondarystructures thus can be advantageously utilized to build vast array ofC-linked carbo β-peptide with a wide variety of substituents with asimilar stable secondary structures in solution.

[0056] Helices in β-peptides: Initial molecular model studies indicatedthat oligomers of β-amino acid (β-peptides) are well suited for adoptionof compact secondary structures stabilized by intramolecular hydrogenbonds. FIG. 6 shows the hydrogen bonds that define the helices obtainedfor a tetrapeptide. These are referred to as 10/12/10 helices, (10, 12,10 refer to the number of bonds between the hydrogen bonding atoms)nomenclature was derived from N-terminal amide hydrogen towards theC-terminal carbonyl group. The tetrapeptide in FIG. 3 has been shown toadopt a 12/10 helical structure with intertwined hydrogen bondedsecondary structure The rigidity of the structure is due to thestereochemical and electronic contributing aspects of the sugar moietyin the tetrapeptide. The incorporation of the sugar motifs in thebackbone carbon of β-amino acid provide not only substantial bulkynessbut also helps in assembly of very small peptides, eventrimers/tetramers, display secondary structure.

[0057] Schemes 1 and 2 exemplify as preferred preparative method of theinvention that provide the amino acid monomers 3 to 10. The aldehyde 1was converted to α, β-unsaturated ester 2 example 1, part 1. Michaeladdition reaction on 2 with benzyl amine, dibenzyl amine and otheramines of the like under basic conditions such as TBAF, DBU,

[0058] DBN, Hunig's base, triethyl amine or other suitable organic basesor metal alkoxides in suitable solvents such as THF or other solvents toget the β-amino acid 3 (Tetrahedron: Asymm. (2002) 13, 21-24). Seeexample 1, part 2 method A, for exemplary reaction conditions. Thecompound thus reported in the invention is a single enantiomer. Forgeneration of 4 a related approach as reported was adopted, for instance(J. Org. Chem. 2001, 16, 1065) to get the mixture of 3 and 4, accordingto the conditions exemplified in example 1, part 2 method B.

[0059] The amino acids represented by the formula 3 and 4 are subjectedto hydrogenolysis in presence of Pd—C in suitable solvents such asmethanol under hydrogen atmosphere to give 5 and 8 respectively asexemplified in example 1, part 3 and part 5 respectively, which wereused as such for further reactions, As exemplified in example 1, part 3and part 7, 3 and 4 are subjected to catalytic hydrogenation andsubsequently with out isolation exposed to (Boc)₂O under basicconditions like triethyl amine in suitable solvents like THF or anyother preferential solvents to result in 5a and 8a, under the conditionsexemplified in example 1, part 4 and part 8 respectively. Compounds 5aand 8a further on hydrolysis under basic conditions with the use of abase like NaOH, LiOH with a suitable normality in preferred solventslike MeOH or otherwise to result in 6 and 9 as exemplified in example 1,part 5 and part 9 respectively for the detailed experimentaldescription. Likewise compounds 5a and 8a were exposed to acids like TFAand the like in solvents for eg; CH₂Cl₂ and the like to providecompounds of formula 7 and 10 respectively as exemplified in example,part 6 and part 10 respectively,

[0060] Synthesis of Peptides Using (S)-Amino Acids

[0061] Scheme 3 exemplifies a preferred preparative method of theinvention that provides compounds of formula 11, 14, 17, 18 and 19representing di, tetra, hexa, octa and tri C-linked carbo β-peptides.Thus in scheme 3, the monomers 5 and 6 are coupled by conventionalreagents such as dicyclohexyl carbodiimide/N-hydroxy succinimide(DCC/HoBt) or 1-ethyl-3-(3′-dimethyl amino prepyl) carbodiimidehydrochloride/N-hydroxy benztriazole (EDCI/HOBt) in solvent phasecoupling procedures (see, example Bodanszky, M-; Bodanszky, A. Thepractice of peptide synthesis; Springer Verlag; New York, 1984) insuitable solvents such as CH₂Cl₂ to result in a dideptide 11. Forexemplary reaction conditions for the preparation of 11 see example 2,part 1.

[0062] Dipeptide 11 was treated with an organic acid like TFA and thelike in suitable solvents for eg; CH₂Cl₂ and the like to provide salt 12as exemplified in example, 2, part 2. Similarly 11 was also subjected tobase induced hydrolysis in presence of suitable base like NaOH and thelike in acceptable solvents like MeOH to finish an unprotected acid 13.For detailed experimental discussion see example 2, part 3. Furthersynthesis of a tetrapeptide was achieved upon coupling of 12 and 13 inpresence of conventional reagents like EDCI/HOBt/DIPEA in suitablesolvents for eg; Cl₂Cl₂ to yield 14 as exemplified in example 2, part 4.Tetrapeptide 14 was subsequently converted to free acid 15 under basichydrolysis conditions with conventional reagents like NaOH in methanol.See example 2, part 5. Also 14 was further exposed to TFA in CH₂Cl₂ todeblock the Boc protecting group and the same was isolated as TFA salt16, as exemplified in example 2, part 6.

[0063] Further preparative methods of other oligomers is depicted inScheme 3. For eg; coupling of 15 with 12 under the above standardreaction conditions (EDCI/HOBt/DIPEA, CH₂Cl₂, DMF) resulted in thehexapeptide 17. For experimental conditions see example 2, part 7.Similarly coupling of 15 with 16 under the conventional peptide couplingreaction conditions as described above, with EDCI in presence ofsolvents like CH₂Cl₂:DMF in ratio as suitable enough for the reaction toresult in the product octamer 18, as exemplified in example 2 part 8.

[0064] A similar preparative description was made use for thepreparation of tri peptide 19 from 13 and 7, under the above saidreaction conditions of EDCI/HOBt in solvents conventionally used inpeptide coupling such as CH₂Cl₂, as exemplified in example 2 part 9.

[0065] Synthesis of Peptides Using S and R Amino Acids

[0066] Scheme 4 exemplifies a preferred preparative method of theinvention that provides compounds of formula 20, 23, 26, 27 and 28representing di, tetra, hexa, octa and tri C-linked carbo β-peptides.Thus in Scheme 4, the monomers 8 and 6 are coupled by conventionalreagents such as dicyclohexyl carbodiimide/N-hydroxy succinimide

[0067] (DCC/HoBt) or 1-ethyl-3-(3′-dimethyl amino prepyl) carbodiimidehydrochloride/N-hydroxy benztriazole (EDCI/HOBt) in solvent phasecoupling procedures (see, example Bodanszky, M-; Bodanszky, A. Thepractice of peptide synthesis; Springer Verlag; New York, 1984) insuitable solvents such as CH₂Cl₂ to result in a dideptide 20. Forexemplary reaction conditions for the preparation of 20 see example 3,part 1.

[0068] Dipeptide 20 was treated with an organic acid like TFA and thelike in suitable solvents for eg; CH₂Cl₂ and the like to provide salt 21as exemplified in example 3, part 2. Similarly 20 was also subjected tobase induced hydrolysis in presence of suitable base like NaOH and thelike in acceptable solvents like MeOH to furnish an unprotected acid 22.For detailed experimental discussion see example 3, part 3.

[0069] Further synthesis of a tetrapeptide was achieved upon coupling of21 and 22 in presence of conventional reagents like EDCI/HOBt/DIPEA insuitable solvents for eg; CH₂Cl₂ to yield 23 as exemplified in example3, part 4. Tetrapeptide 23 was subsequently converted to free acid 24under basic hydrolysis conditions with conventional reagents like NaOHin methanol. See example 3, part 5. Also 23 was further exposed to TFAin CH₂Cl₂ to deblock the Boc protecting group and the same was isolatedas TFA salt 25, as exemplified in example 3, part 6.

[0070] Further preparative methods of other oligomers is depicted inScheme 4. For eg; coupling of 24 with 21 under the above standardreaction conditions (EDCI/HOBt/DIPEA, CH₂Cl₂, DMF) resulted in thehexapeptide 26. For experimental conditions see example 3, part 7.Similarly coupling of 24 with 25 under the conventional peptide couplingreaction conditions as described above, with EDCI in presence ofsolvents like CH₂Cl₂:DMF in ratio as suitable enough for the reaction toresult in the product octamer 27, as exemplified in example 3 part 8.

[0071] A similar preparative description was made use for a thepreparation of tri peptide 28 fom 22 and 7, under the above saidreaction conditions of EDCI/HOBt in solvents conventionally used inpeptide coupling such as CH₂Cl₂, as exemplified in example 3 part 9.

[0072] Synthesis of Peptides from R Amino Acids

[0073] Scheme 5 exemplifies a preferred preparative method of theinvention that provides compounds of formula 29, 32 and 34 representingdi, tetra and hexa C-linked carbo β-peptides. Thus in Scheme 5, themonomers 8 and 9 are coupled by conventional reagents such asdicyclohexyl carbodiimide/N-hydroxy succinimide (DCC/HoBt) or1-ethyl-3-(3′-dimethyl amino prepyl) carbodiimidehydrochloride/N-hydroxy benztriazole (EDCI/HOBt) in solvent phasecoupling procedures (see, example Bodanszky, M-; Bodanszky, A. Thepractice of peptide synthesis; Springer Verlag; New York 1984) insuitable solvents such as CH₂Cl₂ to result in a dideptide 29. Forexemplary reaction conditions for the preparation of 29 see example 4,part 1.

[0074] Dipeptide 29 was treated with an organic acid like TFA and thelike in suitable solvents for eg; CH₂Cl₂ and the like to provide salt 30as exemplified in example 4, part 2. Similarly 29 was also subjected tobase induced hydrolysis in presence of suitable base like NaOH and thelike in an acceptable solvents like MeOH to furnish an unprotected acid31. For detailed experimental discussion see example 4, part 3. Furthersynthesis of a tetrapeptide was achieved upon coupling of 30 and 31 inthe presence of conventional reagents like EDCI/HOBt/DIPEA in suitablesolvents for eg; CH₂Cl₂ to yield 32 as exemplified in example 4, part 4.Tetrapeptide 32 was subsequently converted to free acid 33 under basichydrolysis conditions with conventional reagents like NaOH in methanol.See example 4, part 5.

[0075] Further preparative methods of other oligomers is depicted inScheme 5. For eg; coupling of 33 with 30 under the above standardreaction conditions (EDCI/HOBt/DIPEA, CH₂Cl₂, DMF) resulted in thehexapeptide 34. For experimental conditions see example 4, part 6.

[0076] Synthesis Peptides from R and S Amino Acids

[0077] Scheme 6 exemplifies a preferred preparative method of theinvention that provides compounds of formula 35, 38, 41, 42 and 43representing di, tetra, hexa, octa and tri C-linked carbo β-peptides.Thus in Scheme 6, the monomers 5 and 9 are coupled by conventionalreagents such as dicyclohexyl carbodiimide/N-hydroxy succinimide(DCC/HoBt) or 1-ethyl-3-(3′-dimethyl amino prepyl) carbodiimidehydrochloride/N-hydroxy benztriazole (EDCI/HOBt) in solvent phasecoupling procedures (see, example Bodanszky, M-; Bodanszky, A. Thepractice of peptide synthesis; Springer Verlag; New York, 1984) insuitable solvents such as CH₂Cl₂ to result in a dideptide 35. Forexemplary reaction conditions for the preparation of 35 see example 5,part 1.

[0078] Dipeptide 35 was treated with an organic acid like TFA and thelike in suitable solvents for eg; CH₂Cl₂ and the like to provide salt 36as exemplified in example 5, part 2. Similarly 35 was also subjected tobase induced hydrolysis in presence of suitable base like NaOH and thelike in an acceptable solvents like MeOH to furnish an unprotected acid37. For detailed experimental discussion see example 5, part 3.

[0079] Further synthesis of a tetrapeptide was achieved upon coupling of36 and 37 in presence of conventional reagents like EDCI/HOBt/DIPEA insuitable solvents for eg;

[0080] CH₂Cl₂ to yield 38 as exemplified in example 5, part 4.Tetrapeptide 38 was subsequently converted to free acid 39 under basichydrolysis conditions with conventional reagents like NaOH in methanol.See example 5, part 5. Also 38 was further exposed to TFA in CH₂Cl₂ todeblock the Boc protecting group and the same was isolated as TFA salt40, as exemplified in example 5, part 6.

[0081] Further preparative methods of other oligomers is depicted inScheme 6. For eg; coupling of 40 with 36 under the above standardreaction conditions (EDCI/HOBt/DIPEA, CH₂Cl₂, DMF) resulted in thehexapeptide 41. For experimental conditions see example 5, part 7.Similarly coupling of 39 with 40 under the conventional peptide couplingreaction conditions as described above, with EDCI in presence ofsolvents like CH₂Cl₂:DMF in ratio as suitable enough for the reaction toresult in the product octamer 42, as exemplified in example 5 part 8.Similarly coupling of 37 with 10 under the conventional peptide couplingreaction conditions as described above, with EDCI in presence of solventlike CH₂Cl₂ resulted in the product trimer 43, as exemplified in example5 part 9 (Scheme 6).

[0082] Further synthesis of a tetrapeptide 44 was achieved upon couplingof 22 and 36 in presence of conventional reagents like EDCI/HOBt/DIPEAin suitable solvents for eg; CH₂Cl₂ to yield 44 as exemplified inexample 6, part 1 (Scheme 7). Similarly, as exemplified in example 6,part 2, tetrapeptide 45 was achieved upon coupling of 37 and 21 inpresence of conventional reagents like EDCI/HOBt/DIPEA in suitablesolvents for eg; CH₂Cl₂ to yield 45.

[0083] Scheme 8 exemplifies a preferred preparative method of theinvention that provides compounds of formula 47, 50 arid 52 representingmixed di, tetra and hexa C-linked carbo β-peptides made from 6 andβ-alanine methyl ester 46. Thus in Scheme 8, the monomers 6 and 46 arecoupled by conventional reagents such as dicyclohexylcarbodiimide/N-hydroxy succinimide (DCC/HoBt) in suitable solvents suchas CH₂Cl₂ to result in a dideptide 47. For exemplary reaction conditionsfor the preparation of 47 see example 7, part 1.

[0084] Dipeptide 47 was treated with an organic acid like TFA and thelike in suitable solvents for eg; CH₂Cl₂ and the like to provide salt 48as exemplified in example 7, part 2. Similarly 47 was also subjected tobase induced hydrolysis in presence of suitable base like NaOH and thelike in an acceptable solvents like MeOH to furnish an unprotected acid49. For detailed experimental discussion see example 7, part 3. Furthersynthesis of a tetrapeptide was achieved upon coupling of 48 and 49 inthe presence of conventional reagents like EDCI/HOBt/DIPEA in suitablesolvents for eg; CH₂Cl₂ to yield 50 as exemplified in example 7, part 4.Tetrapeptide 50 was subsequently converted to free acid 51 under basichydrolysis conditions with conventional reagents like NaOH in methanol.See example 7, part 5.

[0085] Further preparative methods of other oligomers is depicted inScheme 8. For eg; coupling of 48 with 51 under the above standardreaction conditions (EDCI/HOBt/DIPEA, CH₂Cl₂, DMF) resulted in thehexapeptide 52. For experimental conditions see example 7, part 6.

[0086] As exemplified in the Schemes 1-8, the synthetic protocolsdeveloped by this invention, numerous C-linked carbo β-peptide class ofcompounds represented by formula I can be synthesised. This new class ofC-linked carbo β-peptides prepared by the method of invention are usefulfor numerous therapeutic applications. As exemplified in the preparativeprocedures, carbo β-peptide class of compounds described in here andrepresented by formula I can be readily prepared. As described in theproeceding secions the compounds that are prepared in the presentinvention are useful for numerous therapeutic applications. In need oftreatment, these compounds can be administered by a variety of ways,such as orally, parentally, intravenously, subcutaneously and otherroutes.

[0087] Conformational Analysis

[0088] 1. NMR Spectroscopy.

[0089] Molecular conformations were investigated by NMR spectroscopy.Such studies were carried out in about 2-8 mM solution in CDCl₃,DMSO-d6, CD₃OH CD₃OD or pyridine-d5. Two-dimensional (2-D) experimentslike TOCSY (Cavanagh. J; Fairbrother. W. J; Palmer, N. J; Protein NMRSpectroscopy; Academic Press San Diego, 1996) and ROESY (Wuthrich, K;NMR of Proteins and Nucleic Acids, Wiley, N.Y., 1986) were obtained onVARIAN -INOVA 500 MHz spectrometer at 30° C. using standard pulsesequences, provided by VARIAN using phase sensitive (States, D. J.;Haberkoom, R. A.; Ruben, D. J, J. Magn. Reson. 48, 286-292, 1982)experiments. Data were processed with Varian VNMR 6.1b software. Thedata for these experiments were collected as 384×2048 matrix, using 8-16scans, per t₁, increment. The data were zero filled and Fouriertransformed as 2k×4k data matrix. Almost all the resonances in thebackbone were very highly resolved in CDCl₃ and could be assigned withthe help of TOCSY and ROESY experiments. TOCSY provided the assignmentswithin the same residue and ROESY provided sequential assignments.

[0090] In these oligomers the N-terminal amides show NOE with intraresidue C_(α)H proton alone, and donot show any inter residue NH/CαH NOElike other amides. This assignment has further been supported from theNOE between the amide and Boc group. Also the C_(α) protons at theC-terminal residue has been identified from the presence of NOE onlywith the self-amide NH.

[0091] Information on Hydrogen Bonding

[0092] a) Solvent Titraton Studies

[0093] In non-polar solvents, titration with a polar solvent is used toassess stability of the structure. Intra-molecularly H-bonded amideproton chemical shifts in CDCl₃ do not change much when a polar hydrogenbond promoting solvents like DMSO-d6 is added upto 33% v/v. Amideprotons, which are not intramolecularly hydrogen bonded, form hydrogenbond with DMSO-d6 and their resonances show large shifts towardsdownfield.

[0094] b) Amide Proton Exchange

[0095] Amide proton exchange is usually used for getting information onintramolecular hydrogen bonding in peptides, which permits to assessconformational stability of peptides. Presence of intramolecularhydrogen bonds results in reduced rate of NH/ND exchange. The amideprotons of the peptide, which are forming intramolecular hydrogenbonding exchanges very slowly in CD₃OD solution, even upto 2-3 days,where as non-hydrogen bonded amides can exchange very fast, sometimeseven with in few minutes.

[0096] c) Variable Temperature Experiments.

[0097] In DMSO-d6, temperature coefficients of the amide proton chemicalshift (Δδ/ΔT in ppb/° K) is used as a signature of intra-molecularhydrogen bond. By varying the temperature the amides chemical shiftsshow small magnitude of temperature coefficients, when they participatein intramolecular hydrogen bonds. Those amides, which are not takingpart in hydrogen bonding, show large magnitude of temperaturecoefficients.

[0098] 2. Circular Dichroism Spectroscopy:

[0099] The circular dichroism (CD) data in the UV region was obtained onJASCO-510 and JASCO-715 instrument at room temperature (nominally 20°C.). The ellipticities are reported as mean residue molar ellipticity,which is obtained by normalizing for the total number of amidechromophores present in the oligomer.

[0100] 3. Molecular Dynamics/Mechanics Studies

[0101] Restrained molecular dynamics data was used to generate 20 lowenergy conformation. The back bone heavy atoms superimposed rather well(RMSD<A⁰). However the C terminal did show fraying. The side chains didshow a larger degree of freedom.

[0102] Results and Discussions:-

[0103] Tetrapeptide-23, Hexapeptide-26 and Octapeptide-27

[0104] Solvent titration studies by adding upto 33% v/v DMSO-d6 in CDCl₃show that apart from the second residue amide [NH (2)] all the amideprotons are hydrogen bonded in both the peptides as they show very small(<0.6 ppm) change in their chemical shifts. This is further supported bya very large range for the amide chemical shifts (about 3 ppm for 23, 26and 27) as well as their very low field shifts (δNH for two amides in26, four amides in 26 and six amides in 27 arm above 7.0 ppm). TheC_(α)H protons also show a very big chemical shift dispersion of about0.7, 0.8 and 0.75 ppm respectively for 23, 26 and 27. The presence of³J_(CαH-CβH) of about 5 Hz or below and 10 Hz and above very clearlydemonstrates that the θ are taking only the g/t conformations. Themolecules take primarily a single value of θ=60°, which is furthersupported by strong inter residue NOE of NH/C_(α)H_((pro-R)),C_(β)H/C_(α)H_((pro-S)).

[0105] The ROESY spectra show very distinctive NOE's corresponding tothe 10/12/10 helices. Specially noteworthy are the medium backbone NOEbetween C_(β)H(2) with NH (4) and C_(α)H_((pro-R)) (4) NOE's in 23,qualifying the 12-membered hydrogen bond. Where as in 23 and 26 severalof these NOE propagate along the helix. For 26 strong C_(β)H (2)/NH (4)and C_(β)H (2)/C_(α)H_((pro-R)) (4) as well as C_(β)H(4)/NH (6) andC_(β)H(4)/C_(α)H_((pro-R)) (6) NOE's are seen. For 27 in addition to theNOE's mentioned for 1 and 2, we observe C_(β)H (6)/NH (8) andC_(β)H(6)/C_(α)H_((pro-R)) (8) NOE peaks. In addition, characteristicweak NOE due to 10-membered hydrogen bonds of the helix between NH(1)/NH (2), NH (3)/NH (4), NH (5)/NH (6) and NH (7)/NH (8) are observedfor 27. Because of the smaller size of 26 only NH (1)/NH (2), NH (3)/NH(4) and NH (5)/NH (6) and for 23 NH (1)/NH (2) and NH (3)/NH (4) interresidue NOE's are observed. In 23, 26 and 27 despite the fact that Bocamide is the first residue, it participates in H-bonding and thusconfirms their remarkable stability. In short α-helices the ends arefrayed in solution. These chirality-controlled oligomers show that thesugar containing β-aminoacids lead to very well defined helices even forpeptides containing only four residues.

[0106] The orientation of sugar rings with respect to the backbone iswell characterized. Excluding residue 2 (R(2)), ³J_(CβH-C4H) is large(≅10 Hz ), corresponding to dihedral angle C_(β)H—C_(β)—C₄—C₄H (χ₁) ofabout 180°. Such an orientation is further supported by NOE's of NH/C₄Hand NH/C_(α)H_((pro-R)). It leaves the sugar ring planes alternatelypointing in opposite direction (opposite to the sense of the screw axisof the helix). The methoxy groups of the odd residues point towards theC terminal, where as those for the even residues, excluding the secondresidue, points towards the N terminal. For residue 2 (R (2)), the³J_(CβH-C4H)=6.0, 5.8 and 6.2 Hz for 23, 26 and 27. This indicates apredominance of conformation with torsion angle|C_(β)H—C_(β)—C₄—C₄H|=60°. The presence of strong NOE ofC₄H/C_(α)H_((pro-S)) and medium NOEs of C₄H/C_(α)H_((pro-S)),C₃H/C_(α)H_((pro-R)) and C₃H/C_(α)H_((pro-S)) enabled us to fix thisangle as −60°.

[0107] The couplings for sugar zing are all very small. The vicinalcoupling constants ³J_(C1H-C2H)≅3 Hz, ³J_(C2H-C3H)≅0 Hz and³J_(C3H-C4H)≅4 Hz correspond to a sugar pucker of ³T₂. Strong NOEbetween Me_((pro-R))/C₁H and Me_((pro-R))/C₂H as well as weakMe_((pro-S))/C₄H. NOE show that the isopropylidene ring exists inenvelop conformation. These observations are also in conformity with thestructure of the sugar unit in several other molecules with C—Cglycosidic linkages.

[0108] The data in DMSO-d6 was also well understood and almost all theNOE's discussed above were obtained. Though the chemical shiftdispersion was not as much as in CDCl₃ and also some of the couplingsindicate little more flexibility in the structure. However, the 10/12/10helix is very well preserved.

[0109] Tripeptide-43, Tetrapeptide-38, Hexapeptide-41 and Octapeptide-42

[0110] The solvent titration studies in CDCl₃ and variable temperaturestudies in DMSO-d6 very clearly show that for 43 and 38 amide protons ofresidue S(2) and R(3) are hydrogen bonded. For 41 the presence of fourhydrogen bonds for amide protons, corresponding to S(2), R(3), S(4) andR(5) is observed and for 42 the presence of six hydrogen bonds for amideprotons S(2), R(3), S(4), R(5), S(6)is observed. The large amidechemical shifts range (e.g., about 3.57 ppm for 7) and low field shiftsof several of them (δ NH upto 8.92 ppm for 7) further support thepresence of large number of hydrogen bonds in this family of molecules.The C_(α)H protons also show very large dispersion of 0.52, 0.93, 1.08and 0.92 ppm for 43, 38, 41 and 42 respectively, additionally confirminga well defined structure for them. Very large (>10 Hz) and very small(often <5 Hz) ³J_(CαH-CβH) values very clearly show that molecule takesprimarily a predominant single conformation with θ=60°. This is ethersupported by strong inter residue NOE between NH/C_(α)H_((Pro-R)),C_(β)H/C_(α)H_((Pro-S)).

[0111] The ROESY spectra show characteristic NOE cross peakscorresponding to the presence of 12/10 helices in 43, 38 and 12/10/12/10helix in 41 and 12/10/12/10/12/10 helix in 42. Strong strength of NOE'sof C_(β)H (1)/NH (3) and C_(β)H (1)/C_(α)H_((pro-R)) (3) and weak NH(2)/NH (3) NOE, in addition to presence of two hydrogen bonded amidesshows the presence of 12/10 helices in 43 and 38. For 41 in addition toabove NOE's, strong intensity NOE's C_(β)H(3)/NH (5) and C_(β)H(3)/C_(α)H_((pro-S)) (5) and weak intensity NH (4)/NH (5) are observed.The above NOE's and participation of NH (2), NH (3), NH (4) and NH (5)in hydrogen bonding confirms the presence of intertwined 12/10/12/10helix for 41. For 42 along with the above mentioned NOE's seen in 4,5and 6 also strong intensity NOE's C_(β)H(5)/NH (7) and C_(β)H(3)/C_(α)H_((pro-S)) (7) and weak intensity NH (6)/NH (7) are observed.The above NOE's and participation of NH (2), NH (3), NH (4), NH (5), NH(6), NH (7) in hydrogen bonding confirms the presence of intertwined12/10/12/10/12/10 helix for 42. Leaving apart the first residue thesugar ring orientation with respect to the backbone also seems to bereasonably well defined. The ³J_(CβH-C4H) of about 10 Hz and theadditional presence of NH/H4 and NH/CαH_((pro-R)) NOE's is in conformityof χ₁ in the vicinity of 180° for these residues. For the first residuethe ³J_(CβH-C4H) is small, being 7.3, 7.2, 6.0 and 6.2 Hz for 43, 38, 41and 42. Averaging due to multiple rotamers may be a plausible cause forthis. The χ₁ of about 180° makes the sugar rings plane alternatelypointing in opposite direction. Thus for 41 the methoxy group at residue3 and 5 point along the C terminus of the helix axis, where as the onesat 2, 4 and 6 point along the helix axis towards the N terminus.Presence of about 2.7 residues per turn causes sugar rings of everyfourth residue to be in each others proximity but slightly displaced byabout 40°.

[0112] In all these molecules the sugar pucker is very well defined. Thecoupling between protons in the ring are: ³J_(C1H-C2H)≅3 Hz,³J_(C2H-C3H)≅0 Hz and ³J_(C3H-C4H)≅4 Hz. These couplings correspond to a³T₂ sugar pucker. Strong NOE, Me_((Pro-R))/C₁H and Me_((Pro-R))/C₂H aswell and weak Me_((Pro-S))/C₄H NOE show that the isopropilidine ringpredominantly takes an envelop conformation. The observations areconsistence with the structure of such a sugar units in other moleculeswith C—C glycocidic linkages.

[0113] The data in DMSO-d6 for 43, 38 and 41 was also well understoodand almost all the NOE's discussed above were obtained. Though thechemical shift dispersion was not as much as in CDCl3 and also some ofthe couplings indicate little more flexibility in the structure.However, the 12/10/12 helix is very well preserved.

[0114] Tetrapeptide-14 and Hexapeptide-17

[0115] No characteristic information on a well-defined structure wasobtained. In CDCl₃ amide protons appeared below δ<7 ppm and solventtitration studies did not show their participation in hydrogen bond. InCD₃OD, amide protons exchanged very quickly and most of them could notbe detected after 12 hours. The consideration of steric and torsionalenergies (Wu et al.) does not support regular 14- or 10/12 helix forthese oligomers

[0116] Tetrapeptide-32, Hexapeptide-34

[0117] In CDCl₃ due to severe overlap in the C_(α)H and C_(β)H region,most of the specific assignments could not be made. Several of the amideresonances appear at low field (δ>7.5 ppm) and solvent titration studiesindicate that many of the amide protons are participating in hydrogenbonding. Since the amide protons are isolated the 3JNH_(βH) couplingcould be obtained. The overlap of resonances in other solvents was moresevere. In CD₃OD amide proton exchange was fast indicating absence ofany structure.

[0118] The following examples are given by way of illustration andtherefore should not be construed to limit the scope of the presentinvention.

Experimental

[0119] General: melting points are uncorrected. CH₂Cl₂ was freshlydistilled from CaH₂ under N₂. DMF was distilled under reduced pressurefrom nindrydrin and stored over 4 A molecular sieves. Triethyl amine wasdistilled from CaH₂ before use. Other solvents and reagents were used asobtained from commercial suppliers. For Boc removal, 10% THF in CH₂Cl₂(checkup) was used. Column chromatography was carried out by using 60 to120 mesh silica gel. Routine ¹H-NMR spectra were obtained on a INOVA-500MHz and 800 MHZ spectrometers and are referenced to residual protonatedNMR solvents. Routine ¹³C-NMR spectra were recorded at 125 MHz and arereferenced to the NMR solvents. High-resolution electron impact massspectrometry (or HRMS-FAB) V G Autospec Mass Spectrometer at 5 or 7 Kresolution using perfluoro kerosene as an internal standard. IR spectrawere recorded on and reported in wavenumbers (cms⁻¹).

[0120] General Procedures (GP)

[0121] GP-1: Debenzylation of Amino Ester

[0122] Benzyl protected amino acid ester (1.0 mmol) was dissolved inmethanol (0.5 mL), treated with 10% Pd—C (0.1 gm for 1.0 g) and stirredat room temperature under hydrogen atmosphere for 12 h. After completionof the reaction (TLC analysis), the reaction mixture was filtered andfiltrate evaporated. The amine was used as such for further reactionswithout purification.

[0123] GP-2: Boc Protection of Amino Esters

[0124] Free amine ester (1.0 mmol) was dissolved in THF (5 mL) andcooled to 0° C. (Boc)₂O (1.0 mmol) in THF (5 mL) was added slowly for 15min. The reaction mixture was allowed to warm to room temperature andstirred for 12 h. THF was evaporated and purified the residue by columnchromatography (Silica gel, 15% EtOAc—pet ether) to give pure Bocprotected amino acid ester.

[0125] GP-3: Hydrolysis of the Amino Acid Ester/Peptide Ester

[0126] A solution of the ester (1.0 mmol) in MeOH (4 mL) was treatedwith 4N NaOH (4 mL) at room temperature. After 2 h, methanol was removedand adjusted to pH 2-3 with aq. 1N HCl and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄) and evaporated to give acid.

[0127] GP4: Boc Deprotection of Amino Acid/Peptide Ester

[0128] A stirred solution of the amino acid ester or peptide ester (0.1g) in dry CH₂Cl₂ (0.9 mL) was treated at 0° C. under nitrogen atmospherewith CF₃COOH (0.1 mL) at room temperature and stirred for 2 h. It wasevaporated and the residue dried under high vacuum. The salts were usedas such without further purification or characterization.

[0129] GP-5: Preparation of Dipeptides from Monomers

[0130] Boc amino acid (1.0 mmol) dissolved in dry. CH₂Cl₂ (3.5 mL) wassequentially treated with HOBt (1.2 mmol) and EDCI (1.2 mmol) at 0° C.After 15 min, free amine ester (1.0 mmol) in dry CH₂Cl₂ (2.5 mL) wasadded to the reaction mixture. The reaction mixture was allowed to reachroom temperature and stirred further for 10 h. It was diluted withCHCl₃, washed with 1N HCl, water, and aq. saturated. NaHCO₃ solution andaq. NaCl solution. The organic layer was dried (Na₂SO₄) and evaporatedto give the dipeptides.

[0131] GP-6: Preparation of Tripeptides Boc protected dipeptide acid(1.0 mmol) dissolved in dry CH₂Cl₂ (6 mL) was treated with HOBt (1.2mmol) and EDCI (1.2 mmol) at 0° C. After 15 min, free amine ester (1.0mmol; obtained by treatment of amine salt (1.0 mmol) with DIPEA (1.5mmol)) in dry CH₂Cl₂ (2.5 mL) was added. It was allowed to reach roomtemperature, and stirred for 10 h. The reaction mixture was diluted withCHCl₃, washed with 1N HCl, water, aq. sat. NaHCO₃ solution and NaClsolution. The organic layer was dried Na₂SO₄) and evaporated to givetripeptide.

[0132] GP-7: Preparation of Tetra Peptides from Dipeptides

[0133] Dipeptide acid (1.0 mmol) dissolved in dry CH₂Cl₂ (6 mL) wastreated with HOBt (1.2 mmol) and EDCI (1.2 mmol) at 0° C. and treatedwith dipeptide amine in dry CH₂Cl₂ (6.5 mL) as described in GP-6 to givetetrapeptide.

[0134] GP-8: Preparation of Hexa Peptides

[0135] Tetra peptide acid (1.0 mmol) dissolved in dry CH₂Cl₂:dry DMF(4:1) (10 mL) was treated with HOBt (1.2 mmol) and EDCI (1.2 mmol) at 0°C. After 15 min., dipeptide amine (1.0 mmol) in dry CH₂Cl₂ (6 mL) wasadded and worked up as described in GP-6 to give hexapeptides.

[0136] GP-9: Preparation of Octa Peptides

[0137] Tetrapeptide acid (1.0 mmol) dissolved in dry CH₂Cl₂: dry DMF(4:1) (10 mL) was treated with HOBt (1.2 mmol) and EDCI (1.2 mmol) at 0°C. After 15 min. tetra peptide amine (1.0 mmol) in dry CH₂Cl₂ (12 mL)was added and work up as described in GP-6 gave octapeptide.

EXAMPLE—1

[0138] Part 1: Unsaturated Ester (Scheme 1; 2)

[0139] Aldehyde 1 (1.95 g, 9.65 mmol) in benzene (10 mL) was added to astirred solution of (methoxy carbonyl methylene) triphenylphosphine(4.84 g, 14.48 mmol) in benzene (10 mL) at reflux and stirring wascontinued for 5 h at same temperature. After reaction benzene wasremoved and crude directly loaded on a flash chromatography column with10% EtOAc in pet.ether to give 2 (1.71 g, 88.7%) as syrup, [α]_(D)=−90.8(c 1.87, CHCl₃), IR (Neat): 2989, 2942, 1725, 1440, 1379, 1260, 1200,1080, 1020, 875 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 6.96 (dd, J=4.8,15.8 Hz,1H, T-C₅H), 6.33 (dd, J=6.9,11.7 Hz, 1H, C—C₅H), 6.18 (dd, J=1.7,15.8Hz, 1H, T-C₆H), 5.97 (d, J=3.8 Hz, 1H, C—C₁H), 5.96 (d, J=3.8 Hz, 1H,T-C₁H), 5.95 (dd, J=1.7, 11.7 Hz, 1H, C—C₆H), 5.64 (ddd, J=1.7, 3.2, 6.9Hz, 1H, C—C₄H), 4.80 (ddd, J=1.7, 3.2, 4.8 Hz, 1H, T-C₄H), 4.62 (d,J=3.8 Hz, 1H, T-C₂H), 4.61 (d, J=3.8 Hz, 1H, C—C₂H), 4.05 (d, J=3.2 Hz,1H, C—C₃H),3.78 (d, J=3.2 Hz, 1H, T-C₃H), 3.74 (s, 3H, T-COOMe), 3.74(s, 3H, C—COOMe), 3.38 (s, 3H, T-OMe), 3.35 (s, 3H, C—OMe), 1.53 (s, 3H,C-Me), 1.51 (s, 3H, T-Me), 1.34 (s, 6H, C&T-Me).

[0140] Method A

[0141] To a stirred solution of 2 (0.86 g, 3.33 mmol) in THF benzylamine(0.36 mL, 3.33 mmol) and DBU (0.50 mL, 3.33 mmol) were added and stirredat room temperature for 8 h.THF was removed and reaction mixture wasdirectly loaded on chromatography column with 15% EtOAc in pet.ether togive 3 (0.72 g, 59.21%) as a syrup.

[0142] Method B

[0143] A stirred solution of 2 (4.0 g, 15.5 mmol) and benzylamine (4.22mL, 38.76 mmol) was stirred at room temperature. After 12 h the reactionmixture was directly loaded on a chromatography column with 10% EtOAc inpet ether to give 4 (1.25 g, 22.1%) as a syrup and 15% EtOAc in pet.ether to give 3 (2.6 g, 45.9%) as a syrup.

[0144] Part 2: Benzyl Protected (S) Amino Acid Ester (Scheme 1; 3)

[0145] [α]_(D)=−31.078 (c 1.0, CHCl₃), IR (Neat): 3370, 2980, 2918,1718, 1449, 1368, 1158, 1072, 1013 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.32(m, 2H, Ar—H), 7.29 (m, 2H, Ar—H), 7.22 (m, 1H, Ar—H), 5.91 (d, J=3.8Hz, 1H, C₁H), 4.59 (d, J=3.9 Hz, 1H, C₂), 4.23 (dd, J=3.2, 8.7 Hz, 1H,C₄H), 3.86 (abq, J=12.9 Hz, 2H, Ar—CH₂), 3.73 (d, J=3.2 Hz, 1H, C₃H),3.69 (s, 3H, —COOMe), 3.41 (dt, J=5.6, 8.7 Hz, 1H, C_(β)H), 3.37 (s, 3H,—OMe), 2.57 (dd, J=5.6, 14.9 Hz, 1H, C_(α)H′), 2.46 (dd, J=5.6,14.9 Hz,1H, C_(α)H), 1.48 (s, 3H, Me), 1.32 (s, 3H, Me). FAB MS: 366 (M⁺+H)

[0146] Part 2: Benzylprotected (R) Amino Acid Ester (Scheme 1; 4)

[0147] [α]_(D)=−35.148 (c 1.0, CHCl₃), IR (Neat): 3340, 2983, 2935,1729, 1455, 1381, 1162, 1074, 1017 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.32(m, 2H, Ar—H), 7.29 (m, 2H, Ar—H), 7.22 (m, 1H, Ar—H), 5.87 (d, J=3.8Hz, 1H, C₁H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.12 (dd, J=3.0, 8.9 Hz, 1H,C₄H), 3.83 (abq, J=14 Hz, 2H, Ar—CH₂), 3.83 (d, J=3.0 Hz, 1H, C₃H), 3.66(s, 3H, —COOMe), 3.44 (ddd, J=4.2, 7.2, 8.9 Hz, 1H, C_(β)H), 3.39 (s,3H, —OMe), 2.80 (dd, J=4.2, 15.6 Hz, 1H, C_(α)H′), 2.57 (dd, J=7.2, 15.6Hz, 1H, C_(α)H), 1.48 (s, 3H, Me), 1.32 (s, 3H, Me). FAB MS: 366 (M⁺+H)

[0148] Part 3: Debenzylation of (S) Amino Acid Ester (Scheme 2; 5)

[0149] Debenzylation of 3 (0.82 g, 2.24 mmol) with 10% Pd—C (0.082 g) inmethanol (2.5 mL) was performed according to GP-1 to obtain amine 5,which was used as such for further reactions without purification.

[0150] Part 4: Debenzylation and Boc Protection of (S) Amino Acid Ester(Scheme 2; 5a)

[0151] Debenzylation of 3 (0.82 g, 2.24 mmol) was performed according toGP-1 to obtain amine 5, which was treated with Boc₂O (0.48 mL, 2.07mmol) as per GP-2 and purified by column chromatography (60-120 meshSilica-gel, 15% EtOAc-pet. ether) to give 5a (0.61 mg, 72%),[α]_(D)=−26.91 (c 1.1, CHCl₃), IR (Neat): 3385, 2980, 2938, 1725, 1705,1502, 1308, 1161, 1071, 1013 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 5.91 (d,J=3.8 Hz, 1H, C₁H), 5.09 (bs, 1H, S—NH), 4.57 (d, J=3.8 Hz, 1H, C₂H),4.30 (m, 1H, C_(β)H), 4.298 (m, 1H, C₄H), 3.68 (d, J=3.1 Hz, 1H, C₃H),3.68 (s, 3H, —COOMe), 3.373 (s, 3H, —OMe), 2.71 (dd, J=3.2, 14.6 Hz, 1H,C_(α)H′), 2.67 (dd, J=7.9, 14.6 Hz, 1H, C_(α)H), 1.48 (s, 3H, Me), 1.43(s, 9H, -Boc), 1.31 (s, 3H, Me). FAB MS: 376 (M⁺+H)

[0152] Part 5: Ester Hydrolysis of (S) Amino Acid Ester (Scheme 2; 6)

[0153] Ester 5a (0.60 g, 1.60 mmol) on hydrolysis with 4N NaOH (6.5 mL)in methanol (6.5 mL) was performed according to GP-3 to give 6 (0.49 g,85%) as a syrup, [α]_(D)=−43.46 (c 1.0, CHCl₃), IR (Neat): 3353, 2980,2925, 1710, 1504, 1313, 1161, 1067, 1012 cm⁻¹; ¹H-NMR (500 MHz, DMSO-d6)δ 6.68 (d, J=8.0 Hz, 1H, S—NH), 5.76 (d, J=3.8 Hz, 1H, C₁H), 4.64 (d,J=3.8 Hz, 1H, C₂H), 4.02 (m, 1H, C_(β)H), 4.02 (m, 1H, C₄H), 3.58 (d,J=3.1 Hz, 1H, C₃H), 3.29 (s, 3H, OMe), 2.29 (dd, J=3.2, 14.6 Hz, 1H,C_(α)H′), 2.23 (dd, J=7.9,14.6 Hz, 1H, C_(α)H), 1.37 (s, 3H, Me), 1.34(s, 9H, -Boc), 1.23 (s, 3H, Me). FAB MS: 384 (M⁺+Na)

[0154] Part 6: Boc Deprotection of (S) Amino Acid Ester (Scheme 2; 7)

[0155] Boc deprotection of 5a (0.207 g, 0.554 mmol) with TFA (0.20 mL)in CH₂Cl₂ (2.0 mL) was performed according to GP-4 to obtain amine salt7, which was used as such for further reactions without purification.

[0156] Part 7: Debenzylation of (R) Amino Acid Ester (Scheme 2; 8)

[0157] Debenzylation of 4 (1.330 g, 3.64 mmol) with 10% Pd—C (0.130 g)in methanol (3.5 mL) was performed according to GP-1 to obtain amine 8,which was used as such for further reactions without purification.

[0158] Part 8: Debenzylation and Boc Protection of (R) Amino Acid Ester(Scheme 2; 8a)

[0159] Debenzylation of 4 (1.330 g, 3.64 mmol) was performed accordingto GP-1 to obtain amine 8, which on treatment with Boc₂O (0.835 mL, 3.64mmol) as per GP-2 and purification by column chromatography (60-120 meshSilica-gel, 15% EtOAc-pet. ether) to give 8a (0.98 g, 72%),[α]_(D)=−25.616 (c 0.48, CHCl₃), IR (Neat): 3374, 2979, 2923, 1718,1499, 1361, 1170,1080, 1016 cm⁻¹; ¹H-NMR (500 MHz,CDCl₃) δ 5.87 (d,J=3.9 Hz, 1H, C₁H), 5.28 (d, J=6.9 Hz, 1H, R—NH), 4.54 (d, J=3.9 Hz, 1H,C₂H), 4.36 (dddd, J=7.7, 6.9, 6.1, 5.0 Hz, 1H, C_(β)H), 4.28 (dd,J=7.7,3.4 Hz, 1H, C₄H), 3.71 (d, J=3.4 Hz, 1H, C₃H), 3.68 (s, 3H,COOMe), 3.40 (s, 3H, OMe), 2.71 (dd, J=6.1,15.6 Hz, 1H, C_(α)H′), 2.66(dd, J=5.0,15.6 Hz, 1H, C_(α)H), 1.47 (s, 3H, Me), 1.43 (s, 9H, -Boc),1.31 (s, 3H, Me). FAB MS: 376 (M⁺+H)

[0160] Part 9: Ester Hydrolysis of (R) Amino Acid Ester (Scheme 2; 9)

[0161] Hydrolysis of ester 8a (0.980 g, 2.61 mmol) with 4N NaOH (10.5mL) in methanol (10.5 mL) was performed according to GP-3 to give 9(0.815 g, 84%) as a white solid, M.p. 124-127° C.; [α]_(D)=−22.540 (c0.55, CHCl₃), IR (KBr): 3324, 2983, 2929, 1708, 1643, 1410, 1262, 1160,1076, 1018 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 5.88 (d, J=3.8 Hz, 1H, C₁H),5.33 (d, J=9.4 Hz, 1H, R—NH), 4.55 (d, J=3.8 Hz, 1H, C₂H), 4.37 (dddd,J=9.4, 7.6, 5.6, 4.9 Hz, 1H, C_(β)H), 4.32 (dd, J=7.6, 2.6 Hz, 1H, C₄H),3.73 (d, J=2.6 Hz, 1H, C₃H), 3.41 (s, 3H, OMe), 2.77 (dd, J=5.6, 16.2Hz, 1H, C_(α)H), 2.72 (dd, J=4.9,16.2 Hz, 1H, C_(α)H′), 1.48 (s, 3H,Me), 1.44 (s, 9H, -Boc), 1.32 (s, 3H, Me). FAB MS: 362 (M⁺+H).

[0162] Part 10: Boc Deprotection of (R) Amino Acid Ester (Scheme 2; 10)

[0163] Boc deprotection of 8a (0.275 g, 0.73 mmol) with TFA (0.28 mL) inCH₂Cl₂ (2.5 mL) was performed according to GP-4 to obtain salt 10.

EXAMPLE—2

[0164] Part 1: Preparation of Dipeptide (Scheme 3; 11)

[0165] Acid 6 (0.426 g, 1.18 mmol) was treated with HOBt (0.19 g, 1.45mmol), EDCI (0.27 g, 1.45 mmol) and 5 (prepared by debenzylation of 3(0.432 g 1.18 mmol) with 10% Pd—C (43 mg) according to GP-1) accordingto GP-5 and purified by column chromatography (60-120 mesh Silica-gel,50% EtOAc-pet. ether) to give 11 (0.545 g, 75%) as a white solid, M.p.75-78° C.; [α]_(D)=−48.21 (c 0.5, CHCl₃), IR (KBr): 3365, 2985, 2941,1741, 1686, 1520, 1365, 1164, 1075, 1012 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ6.36 (d, J=8.2 Hz, 1H, S₂—NH), 5.99 (d, J=3.9 Hz, 1H, C₁H), 5.91 (d,J=3.9 Hz, 1H, C₁H), 5.60 (d, J=8.1 Hz, 1H, S₁—NH), 4.60 (m, 1H, C_(β)H),4.59 (d, J=3.9 Hz, 1H, C₂H), 4.58 (d, J=3.9 Hz, 1H, C₂H), 4.35 (m, 1H,C₄H), 4.21 (m, 1H, C_(β)H), 4.21 (m, 1H, C₄H), 3.82 (d, J=3.3 Hz, 1H,C₃H), 3.75 (d, J=3.3 Hz, 1H, C₃H), 3.68 (s, 3H, —COOMe), 3.41 (s, 3H,—OMe), 3.38 (s, 3H, OMe), 2.68 (dd, 1H, J=7.3, 15.6 Hz, C_(α)H′), 2.61(dd, J=5.3, 15.6 Hz, 1H, C_(α)H), 2.44 (dd, J=4.7, 14.1 Hz, 1 H, CαH′),2.36 (dd, J=4.1, 14.1 Hz, C_(α)H), 1.48 (s, 3H, Me), 1.46 (s, 3H, Me),1.44 (s, 9H, -Boc), 1.32 (s, 3H, Me), 1.30 (s, 3H, Me). FAB MS: 619.2(M⁺+H)

[0166] Part 2: Boc Deprotectin of Dipetide (Scheme 3; 12)

[0167] Boc deprotection of 11 (0.67 g, 1.08 mmol) with TFA (0.7 mL) inCH₂Cl₂ (7 mL) was performed according to GP-4 to give the amine salt 12.

[0168] Part 3: Ester Hydrolysis of Dipeptide (Scheme 3; 13)

[0169] Hydrolysis of ester 11 (0.40 g, 0.65 mmol) with 4N NaOH (2.5 mL)in methanol (2.5 mL) was performed according to GP-3 to give 13 (0.365g, 94%) as a solid, M.p. 64-66° C.; [α]_(D)=−54.22 (c 0.7, CHCl₃), IR(KBr): 3365, 2986, 2940, 1723, 1678, 1519, 1368, 1166, 1074, 1015 cm⁻¹;¹H-NMR (500 MHz, DMSO-d6) δ 7.79 (d, J=8.7 Hz, 1H, S₂—NH), 6.26 (d,J=8.1 Hz, 1H, S₁—NH), 5.78 (d, J=3.9 Hz, 1H, C₁H), 5.75 (d, J=3.9 Hz,1H, C₁H), 4.63 (d, J=3.9 Hz, 1H, C₂H), 4.61 (d, J=3.9 Hz, 1H, C₂H), 4.3(m, 1H, C_(β)H), 4.19 (m, 1H, C₄H), 4.04 (m, 1H, C₄H), 3.96 (m, 1H,C_(β)H), 3.63 (d, J=3.3 Hz, 1H, C₃H), 3.59 (d, J=3.3 Hz, 1H, C₃H), 3.30(s, 3H, OMe), 3.29 (s, 3H, OMe), 2.34 (m, 2H, C_(α)H′,H), 2.21(m, 2H,C_(α)H′,H), 1.48 (s, 3H, Me), 1.46 (s, 3H, Me), 1.44 (s, 9H, -Boc), 1.32(s, 3H, Me), 1.30 (s, 3H, Me). FAB MS: 605 (M⁺+H)

[0170] Part 4: Preparation of Tetrapeptide (Scheme 3; 14)

[0171] Acid 12 (0.655 g, 1.08 mmol) was treated with HOBt (0.176 g, 1.30mmol), EDCI (0.25 g, 1.30 mmol), 13 (prepared by Boc deprotection of 11(0.67 g, 1.08 mmol) with TFA (0.7 mL) in CH₂Cl₂ (7 mL) according toGP-4) and DIPEA (0.45 mL, 1.63 mmol) according to GP-7 and purified bycolumn chromatography (60-120 mesh Silica-gel, 2.0% Methanol-CHCl₃) togive 14 (0.9 g, 75%) as a white solid, M.p. 124-126° C.; [α]_(D)=−36.79(c 0.25, CHCl₃), IR (KBr): 3372, 3392.5, 2982, 2933, 1671, 1530, 1369.5,1169, 1070, 1012 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 6.81 (d, J=7.9 Hz, 1H,S₄—NH), 6.79 (d, J=7.9 Hz, 1H, S₃—NH), 6.57 (d, J=7.9 Hz, 1H, S₂—NH),5.92 (d, J=3.9 Hz, 1H, C₁H), 5.895 (d, J=3.9 Hz, 1H, C₁H), 5.89 (d,J=3.9 Hz, 1H, C₁H), 5.88 (d, J=3.9 Hz, 1H, C₁H), 5.58 (d, J=6.1 Hz, 1H,S₁—NH), 4.59 (m, 1H, C_(β)H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.57 (d,J=3.9 Hz, 1H, C₂H), 4.56 (d, J=3.9 Hz,1H, C₂H), 4.56 (d, J=3.9 Hz, 1H,C₂H), 4.59 (m, 1H, C_(β)H), 4.53 (m, 1H, C_(β)H), 4.36 (m, 1H, C₄H),4.32 (m, 1H, C₄H), 4.29 (m, 1H, C₄H), 4.25 (m, 1H, C_(β)H), 4.25 (m, 1H,C₄H), 3.86 (d, J=3.1 Hz, 1H, C₃H), 3.80 (d, J=2.9 Hz, 1H, C₃H), 3.78 (d,J=3.0 Hz, 1H, C₃H), 3.68 (s, 3H, —COOMe), 3.67 (d, J=3.1 Hz, 1H, C₃H),3.40 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.37 (s, 3H,OMe), 2.67 (dd, J=5.8, 15.6 Hz, 1H, C_(α)H′), 2.59 (dd, J=5.8,15.6 Hz,1H, C_(α)H), 2.46 (m, 2H, C_(α)H,H′), 2.43 (m, 2H, C_(α)H,H′), 2.42 (m,2H, C_(α)H,H′), 1.47 (s, 3H, Me), 1.465 (s, 3H, Me),1.46 (s, 6H, 2-Me),1.43 (s, 9H, -Boc), 1.31 (s, 3H, Me), 1.302 (s, 3H, Me), 1.30 (s, 6H,2-Me). FAB MS: 1105.1 (M⁺+H)

[0172] Part 5: Ester Hydrolysis of Tetrapeptide (Scheme 3; 15)

[0173] Hydrolysis of ester 14 (0.6 g, 0.54 mmol) with 4N NaOH (2 mL) inmethanol (2 mL) was performed according to GP-3 to give 15 (0.42 g, 71%)as a solid, M.p. 141-143° C.; [α]_(D)=−45.72 (c 0.6, CHCl₃), IR (KBr):3397, 2986, 2937.5, 1656, 1527, 1378, 1167, 1080, 1021 cm⁻¹; ¹H-NMR (500MHz, DMSO-d6) δ 7.88 (d, J=7.9 Hz, 1H, S₄—NH), 7.55 (d, J=7.9 Hz, 1H,S₃—NH), 7.44 (d, J=7.9 Hz, 1H, S₂—NH), 6.25 (d, J=6.1 Hz, 1H, C₁H), 5.77(d, J=3.9 Hz, 1H, C₁H), 5.76 (d, J=3.9 Hz, 1H, C₁H), 5.75 (d, J=3.9 Hz,1H, C₁H), 5.75 (d, J=3.9 Hz, 1H, C₁H), 4.65 (d, J=3.9 Hz, 1H, C₂H), 4.62(d, J=3.9 Hz, 1H, C₂H), 4.61 (d, J=3.9 Hz, 1H, C₂H), 4.60 (d, J=3.9 Hz,1H, C₂H), 4.32 (m, 1H, C_(β)H), 4.31 (m, 1H, C_(β)H), 4.29 (m, 1H,C_(β)H), 4.21 (m, 1H, C₄H), 4.16 (m, 1H, C₄H), 4.12 (m, 1H, C₄H), 4.06(m, 1H, C₄H), 3.98 (m, 1H, C_(β)H),3.69 (d, J=3.1 Hz, 1H, C₃H), 3.67 (d,J=2.9 Hz, 1H, C₃H), 3.63 (d, J=3.0 Hz, 1H, C₃H), 3.62 (s,1H, C₃H), 3.30(s, 6H, OMe), 3.294 (s, 3H, OMe), 3.29 (s, 3H, OMe), 2.35 (m,1H,C_(α)H′), 2.29 (m,1H, C_(α)H), 2.25(m, 2H, C_(α)H,H′), 2.26 (m, 1H,C_(α)H′), 2.23 (m, 1H, C_(α)H), 2.20 (m, 1H, C_(α)H′), 2.17 (m, 1H,C_(α)H), 1.38 (s, 3H, Me), 1.37 (s, 3H, Me),1.36 (s, 3H, Me), 1.35 (s,9H, -Boc), 1.35 (s, 3H, Me), 1.24 (s, 3H, Me), 1.232 (s, 3H, Me), 1.224(s, 6H, 2-Me). FAB MS: 1113.2 (M⁺+Na)

[0174] Part 6: Boc Deprotectin of Tetrapeptide (Scheme 3; 16)

[0175] Boc deprotection of 14 (0.101 g, 0.092 mmol) with TFA (0.1 mL) inCH₂Cl₂ (1.0 mL) according to GP-4 gave 16.

[0176] Part 7: Preparation of Hexapeptide (Scheme 3; 17)

[0177] Acid 15 (0.15 g, 0.138 mmol) was treated with HOBt (0.023 g,0.165 mmol), EDCI (0.032 g, 0.165 mmol), 12 (prepared by Bocdeprotection of 14 (0.085 g, 0.138 mmol) with TFA (0.1 mL) in CH₂Cl₂ (1mL) as described in GP-4) and DIPEA (0.04 mL, 0.207) according to GP-8and purified by column chromatography (60-120 mesh Silica gel, 2.5%Methanol-CHCl₃) to give 17 (0.122 g, 56%) as a white solid, M.p.140-142° C.; [α]_(D)=−30.46 (c 0.6, CHCl₃), IR (KBr): 3377, 2987.5,2938, 1664, 1528, 1376, 1217, 1166, 1080, 1022 cm⁻¹; ¹H-NMR (500 MHz,CDCl₃) δ 6.92 (d, J=7.9 Hz, 1H, S₅—NH), 6.86 (d, J=7.9 Hz, 1H, S₆—NH),6.85 (d, J=7.9 Hz, 1H, S₄—NH), 6.71 (d, J=7.9 Hz, 1H, S₃—NH), 6.58(d,J=7.9 Hz, 1H, S₂—NH), 5.92 (d, J=3.9 Hz, 1H, C₁H), 5.895 (d, J=3.9Hz,1H, C₁H), 5.89 (d, J=3.9 Hz, 1H, C₁H), 5.89 (d, J=3.9 Hz, 1H, C₁H),5.88 (d, J=3.9 Hz, 1H, C₁H), 5.64 (d, J=6.1 Hz,1H, S₁—NH), 4.59 (m, 1H,C_(β)H), 4.55 (m, 1H, C_(β)H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.57 (d,J=3.9 Hz, 1H, C₂H), 4.56 (d, J=3.9 Hz,1H, C₂H), 4.56 (d, J=3.9 Hz, 1H,C₂H), 4.54 (m,1H, C_(β)H), 4.53 (m, 1H, C_(β)H), 4.50 (m,1H, COH), 4.38(m, 1H, C₄H), 4.33 (m, 1H, C₄H), 4.32 (m, 1H, C₄H), 4.31 (m, 1H, C₄H),4.30 (m, 1H, C₄H), 4.25 (m, 1H, C_(β)H), 4.25 (m, 1H, C₄H), 3.86 (d,J=3.1 Hz, 1H, C₃H), 3.82 (d, J=2.9 Hz, 1H, C₃H), 3.79 (d, J=2.9, 2H,2-C₃H), 3.77 (d, J=3.0 Hz, 1H, C₃H), 3.68 (s, 3H, —COOMe), 3.67 (d,J=3.1, 1H, C₃H), 3.40 (s, 6H, 2-OMe), 3.39 (s, 3H, OMe), 3.38 (s, 6H,2-OMe), 3.37 (s, 3H, OMe), 2.67 (dd, J=5.8, 15.6 Hz, 1H, C_(α)H′), 2.59(dd, J=5.8, 15.6 Hz, 1H, C_(α)H), 2.46 (m, 2H, C_(α)H,H′), 2.43 (m, 2H,C_(α)H,H′), 2.42 (m, 2H, C_(α)H,H′), 1.474 (s, 3H, Me), 1.465 (s, 3H,Me),1.46 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.31 (s, 3H, Me), 1.302 (s,3H, Me), 1.30 (s, 3H, Me). FAB MS: 1592.6 (M⁺+H)

[0178] Part 8: Preparation of Octapeptide (Scheme 3; 18)

[0179] Acid 15 (0.10 g, 0.092 mmol) was treated with HOBt (0.015 g, 0.11mmol), EDCI (0.02 g, 0.11 mmol), 16 (prepared by Boc deprotection of 14(0.101 g, 0.092 mmol) with TFA (0.1 mL) in CH₂Cl₂ (1.0 mL) according toGP-4) and DIPEA (0.024 mL, 0.14) according to GP-9 and purified bycolumn chromatography (60-120 mesh Silica-gel, 3.0% Methanol-CHCl₃) togive 18 (0.075 g, 39%) as a white solid, M.p. 156-159° C.;[α]_(D)=−25.58 (c 0.45, CHCl₃), IR (KBr): 3378, 2992, 2932, 1667, 1564,1370, 1156, 1068, 1011 cm⁻¹; FAB MS: 2078.2 (M⁺+H)

[0180] Part 9: Preparation of Tripeptide (Scheme 3; 19)

[0181] Acid 13 (0.335 g, 0.554 mmol) was treated with HOBt (0.090 g,0.665 mmol), EDCI (0.127 g, 0.665 mmol), 7 prepared by Boc deprotectionof 5a (0.208 g, 0.554 mmol) with TFA (0.2 mL) in CH₂Cl₂ (2.0 mL)according to GP-4) and DIPEA (0.15 mL, 0.831 mmol) according to GP-6 andpurified by column chromatography (60-120 mesh Silica-gel, 75%EtOAc-pet. ether) to give 19 (0.380 g, 80%) as a white solid, M.p.95-98° C.; [α]_(D)=−39.52 (c 0.5, CHCl₃), IR (KBr): 3397, 2994, 2935,1740, 1677, 1521, 1371, 1161, 1074, 1014 cm⁻¹; ¹H-NMR (500 MHz, CDCl3) δ6.56 (d, J=8.1 Hz, 1H, S₂—NH), 6.56 (d, J=8.1 Hz, 1H, S₃—NH), 5.92 (d,J=3.9 Hz, 1H, C₁H), 5.91 (d, J=3.9 Hz, 1H, C₁H), 5.91 (d, J=3.9 Hz, 1H,C₁H), 5.58 (d, J=8.1 Hz, 1H, S₁—NH), 4.60 (m, 1H, C_(β)H), 4.57 (d,J=3.9 Hz, 1H, C₂H), 4.56 (d, J=3.9 Hz, 1H, C₂H), 4.55 (d, J=3.9 Hz, 1H,C₂H), 4.55 (m, 1H, C_(β)H), 4.37 (m, 1H, C₄H), 4.35 (m, 1H, C₄H), 4,25(m, 1H, C_(β)H), 4.25 (m, 1H, C₄H), 3.85 (d, J=3.3 Hz, 1H, C₃H), 3.79(d, J=3.3 Hz, 1H, C₃H), 3.75 (d, J=3.3 Hz, 1H, C₃H), 3.68 (s, 3H,—COOMe), 3.40 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 2.67(m, 1H, C_(α)H′), 2.58 (m, 1H, C_(α)H), 2.46 (m, 1H, C_(α)H′), 2.41 (m,1H, C_(α)H′,H), 2.38 (m,1H, C_(α)H),1.49 (s, 3H, Me), 1.47 (s, 3H, Me),1.47 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.32 (s, 3H, Me), 1.30 (s, 3H,2-Me). FAB MS: 884 (M⁺+Na)

EXAMPLE—3

[0182] Part 1: Preparation of Dipeptide (Scheme 4; 20) Acid 6 (1.2 g,3.32 mmol) was treated with HOBt (0.54 g, 4 mmol), EDCI (0.765 g, 4mmol) and 8 (prepared by debenzylation of 4 (1.21 g 3.32 mmol) with 10%Pd—C (0.12 g) according to GP-1) according to GP-5 and purified bycolumn chromatography (60-120 mesh Silica-gel, 50% EtOAc-pet ether) togive 20 (1.55 g, 76%) as a white solid, M.p. 73-76° C.; [α]_(D)=−37.414(c 0.46, CHCl₃), IR (KBr): 3391, 2975, 2934, 1740, 1690, 1648, 1528,1372, 1170, 1074, 1015 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 6.70 (d, J=8.9Hz, 1H, R₂—NH), 5.92 (d, J=3.8 Hz, 1H, C₁H), 5.89 (d, J=3.8 Hz, 1H,C₁H), 5.23 (d, J=7.5 Hz, 1H, S₁—NH), 4.7 (dddd, J=8.9, 7.7, 6.3, 5.3 Hz,1H, C_(β)H), 4.57 (d, J=3.8 Hz, 1H, C₂H), 4.54 (d, J=3.8 Hz, 1H, C₂H),4.31 (dd, J=7.7, 3.2 Hz, 1H, C₄H), 4.29 (dd, J=6.5, 3.2 Hz, 1H, C₄H),4.16 (dddd, J=7.5, 6.5, 5.6, 5.4 Hz, 1H, C_(β)H), 3.75 (d, J=3.2 Hz, 1H,C₃H), 3.73 (d, J=3.2 Hz, 1H, C₃H), 3.68 (s, 3H, COOMe), 3.41 (s, 3H,OMe), 3.37 (s, 3H, OMe), 2.69 (dd, J=6.3, 15.9 Hz, 1H, C_(α)H′), 2.62(dd, J=5.3,15.9 Hz, 1H, C_(α)H), 2.52 (dd, J=5.4, 14.9 Hz, C_(α)H), 2.41(dd, J=5.6, 14.9 Hz, C_(α)H), 1.48 (s, 3H, Me), 1.47 (s, 3H, Me), 1.43(s, 9H, -Boc), 1.314 (s, 3H, Me), 1.31 (s, 3H, Me). FAB MS: 619.3 (M⁺+H)

[0183] Part 2: Boc Deprotectin of Dipetide (Scheme 4; 21)

[0184] Boc deprotection of 20 (0.42 g, 0.68 mmol) with TFA (0.4 mL) inCH₂Cl₂ (4 mL) was performed according to GP-4 to give the amine salt 21.

[0185] Part 3: Ester Hydrolysis of Dipeptide (Scheme 4; 22)

[0186] Hydrolysis of ester 20 (1.05 g, 1.7 mmol) with 4N NaOH (6.7 mL)in methanol (6.7 mL) was performed accorxling to GP-3 to give 22 (0.86g, 84%) as a solid, M.p. 107-109° C.; [α]_(D)=−38.709 (c 0.41, CHCl₃),IR (KBr): 3374, 2980, 2939.5, 1705, 1662, 1529, 1370.5, 1161, 1079, 1011cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.02 (d, J=8.5 Hz, 1H, R₂—NH), 5.90 (d,J=3.8 Hz, 1H, C₁H), 5.89 (d, J=3.8 Hz, 1H, C₁H), 5.27 (d, J=7.7 Hz, 1H,S₁—NH), 4.67 (m, 1H, C_(β)H), 4.58 (d, J=3.8 Hz, 1H, C₂H), 4.55 (d,J=3.8 Hz, 1H, C₂H), 4.34 (dd, J=6.6, 3.1 Hz, 1H, C₄H), 4.28 (dd, J=8.0,3.1 Hz, 1H, C₄H), 4.16 (dddd, J=8.0, 7.7, 6.2, 5.2 Hz, 1H, C_(β)H), 3.78(d, J=3.1 Hz, 1H, C₃H), 3.73 (d, J=3.1 Hz, 1H, C₃H), 3.41(s, 3H, OMe),3.38 (s, 3H, OMe), 2.71 (m, 2H, C_(α)H,C_(α)H′), 2.53 (dd, J=5.2,14.9Hz, 1H, C_(α)H′), 2.43 (dd, J=6.2, 14.9 Hz, C_(α)H), 1.48 (s, 3H, Me),1.47 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.31 (s, 6H, Me). FAB MS: 605.2(M⁺+H)

[0187] Part 4: Preparation of Tetrapeptide (Scheme 4; 23)

[0188] Acid 22 (0.41 g, 0.68 mmol) was treated with HOBt (0.11 g, 0.82mmol), EDCI (0.16 g, 0.82 mmol), 21 (prepared by Boc deprotection of 20(0.42 g, 0.68 mmol) with TFA (0.4 mL) in CH₂Cl₂ (4 mL) according toGP-4) and DIPEA (0.18 mL, 1.02 mmol) according to GP-7 and purified bycolumn chromatography (60-120 mesh Silica-gel, 1.5% Methanol-CHCl₃) togive 23 (0.57 g, 76%) as a white solid, M.p. 124-127° C.; [α]_(D)=−15.18(c 0.3, CHCl₃), IR (KBr): 3366, 3286, 2987, 2936, 1718, 1655, 1541,1374, 1211, 1166, 1081, 1021 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 8.16 (d,J=8.2 Hz, 1H, R₄—NH), 7.06 (d, J=9.1 Hz, 1H, S₃—NH), 6.76 (d, J=10.0 Hz,1H, R₂—NH), 5.91 (d, J=8.9 Hz, 1H, S₁—NH), 5.89 (d, J=4.0 Hz, 1H, C₁H),5.88 (d, J=3.7 Hz, 1H, C₁H), 5.87 (d, J=3.7 Hz, 1H, C₁H), 5.87 (d, J=3.7Hz, 1H, C₁H), 4.84 (M, 1H, C_(β)H), 4.63 (m, 1H, C_(β)H), 4.57 (d, J=4.0Hz, 1H, C₂H), 4.55 (d, J=3.7 Hz, 1H, C₂H), 4.53 (d, J=3.7 Hz, 1H, C₂H),4.51 (d, J=4.0 Hz, 1H, C₂H), 4.41 (m, 1H, C_(β)H), 4.36 (dd, J=3.8, 8.8Hz, 1H, C₄H), 4.29 (dd, J=3.1, 9.9 Hz, 1H, C₄H), 4.14 (m, 1H, C_(β)H),4.13 (dd, J=2.8, 9.4 Hz, 1H, C₄H), 4.11 (dd, J=3.4, 6.2 Hz, 1H, C₄H),4.09 (d, J=3.1 Hz, 1H, C₃H), 3.80 (d, J=2.9 Hz, 1H, C₃H), 3.78 (d, J=3.4Hz, 1H, C₃H), 3.73 (d, J=3.4 Hz, 1H, C₃H), 3.66 (s, 3H, —COOMe), 3.41(s, 3H, OMe), 3.37 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.36 (s, 3H, OMe),2.83 (dd, J=3.2, 12.9 Hz, 1H, C_(α)H), 2.66 (dd, J=2.3, 12.7 Hz, 1H,C_(α)H), 2.51 (dd, J=9.7, 12.9 Hz, 1H, C_(α)H), 2.44 (dd, J=5.3, 13.0Hz, 1H, C_(α)H), 2.43 (dd, J=4.1, 12.8 Hz, 1H, C_(α)H′), 2.41 (dd,J=5.2, 12.8 Hz, 1H, C_(α)H′), 2.18 (dd, J=3.6, 13.0 Hz, 1H, C_(α)H′),2.13 (dd, J=10.9, 12.7 Hz, 1H, C_(α)H′), 1.49 (s, 3H, Me), 1.44 (s, 3H,Me), 1.44 (s, 9H, Boc), 1.43 (s, 3H, Me), 1.30 (s, 3H, Me), 1.30 (s, 3H,Me), 1.30 (s, 3H, Me), 1.29 (s, 3H, Me), 1.26 (s, 3H, Me). FAB MS:1105.3 (M⁺+H)

[0189] Part 5: Ester Hydrolysis of Tetrapeptide (Scheme 4; 24)

[0190] Hydrolysis of ester 23 (0.35 g, 0.32 mmol) with 4N NaOH (1.2 mL)in methanol (1.2 mL) was performed according to GP-3 to give 24 (0.30 g,88%) as a solid, M.p. 139-142° C.; [α]_(D)=−33.552 (c 0.4, CHCl₃), IR(KBr): 3344, 2988, 2938, 1718.5, 1663, 1527, 1376, 1217, 1166, 1081,1020 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.65 (d, J=8.2 Hz, 1H, R₄—NH), 7.23(d, J=9.1 Hz, 1H, S₃—NH), 6.99 (d, J=10.0 Hz, 1H, R₂—NH), 5.90 (d, J=3.9Hz, 1H, C₁H), 5.89 (d, J=4.0 Hz, 1H, C₁H), 5.88 (d, J=3.7 Hz, 1H, C₁H),5.87 (d, J=3.7 Hz, 1H, C₁H), 5.64 (d, J=9.5 Hz, 1H, S₁—NH), 4.70 (m, 1H,C_(β)H), 4.69 (m, 1H, C_(β)H), 4.59 (d, J=4.0 Hz, 1H, C₂H), 4.56 (d,J=3.7 Hz, 1H, C₂H), 4.55 (d, J=3.7 Hz, 1H, C₂H), 4.54 (d, J=4.0 Hz, 1H,C₂H), 4.45 (m, 1H, C_(β)H), 4.35 (dd, J=3.8, 8.8 Hz, 1H, C₄H), 4.31 (dd,J=3.1, 9.9 Hz, 1H, C₄H), 4.29 (dd, J=3.1, 9.9 Hz, 1H, C₄H), 4.26 (dd,J=2.8, 9.4 Hz, 1H, C₄H), 4.17 (m, 1H, C_(β)H), 3.97 (d, J=3.1 Hz, 1H,C₃H), 3.85 (d, J=2.9 Hz, 1H, C₃H), 3.79 (d, J=3.4 Hz, 1H, C₃H), 3.75 (d,J=3.4 Hz, 1H, C₃H), 3.41 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.38 (s, 3H,OMe), 3.36 (s, 3H, OMe), 2.81 (dd, J=3.2, 12.9 Hz, 1H, C_(α)H), 2.62(dd, J=2.3, 12.7 Hz, 1H, C_(α)H), 2.52 (dd, J=9.7, 12.9 Hz, 1H,C_(α)H′), 2.51 (dd, J=5.3, 13.0 Hz, 1H, C_(α)H), 2.48 (dd, J=4.1, 12.8Hz, 1H, C_(α)H), 2.46 (dd, J=5.2, 12.8 Hz, 1H, C_(α)H′), 2.36 (dd,J=3.6, 13.0 Hz, 1H, C_(α)H′), 2.28 (dd, J=3.6, 13.0 Hz, 1H, C_(α)H),1.49 (s, 3H, Me), 1.486 (s, 3H, Me), 1.48 (s, 3H, Me),1.46 (s, 3H,Me),1.44 (s, 9H, Boc), 1.31 (s, 6H, 2XMe); 1.302 (s, 3H, Me), 1.30 (s,3H, Me). FAB MS: 1113.2 (M⁺+Na)

[0191] Part 6: Boc Deprotectin of Tetrapetide (Scheme 4; 25)

[0192] Boc deprotection of 24 (0.16 g, 0.14 mmol) with TFA (0.15 mL) inCH₂Cl₂ (1.5 mL) according to GP-4 gave 25.

[0193] Part 7: Preparation of Hexapeptide (Scheme 4; 26)

[0194] Acid 24 (0.1 g, 0.09 mmol) was treated with HOBt (0.015 g, 0.11mmol), EDCI (0.022 g, 0.11 mmol), 21 (prepared by Boc deprotection of 20(0.057 g, 0.09 mmol) with TFA (0.1 mL) in CH₂Cl₂ (1 mL) as described inGP-4) and DIPEA (0.03 mL, 0.14 mmol) according to GP-8 and purified bycolumn chromatography (60-120 mesh Silica gel, 2.0% Methanol-CHCl₃) togive 26 (0.085 g, 58%) as a white solid, M.p. 114-116° C.; [α]_(D)=+7.59(c 0.35, CHCl₃), IR (KBr): 3381, 2986, 2934, 1716, 1651, 1557.5, 1374,1166, 1081, 1022 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 8.75 (d, J=9.6 Hz, 1H,R₄—NH), 8.62 (d, J=9.6 Hz, 1H, R₆—NH) 7.69 (d, J=9.9 Hz, 1H, S₃—NH),7.30 (d, J=8.7 Hz, 1H, S₅—NH), 6.71 (d, J=10.2 Hz, 1H, R₂—NH), 6.10 (d,J=7.3 Hz, 1H, S₁—NH), 5.94 (d, J=3.8 Hz, 1H, C₁H), 5.89 (d, J=3.7 Hz,1H, C₁H), 5.88 (d, J=4.0 Hz, 1H, C₁H), 5.87 (d, J=3.7 Hz, 1H, C₁H), 5.79(d, J=3.8 Hz, 1H, C₁H), 5.78 (d, J=3.8 Hz, 1H, C₁H), 5.10 (m, 1H,C_(β)H), 4.70 (m, 1H, C_(β)H), 4.60 (m, 1H, C_(β)H), 4.59 (d, J=3.7 Hz,1H, C₂H), 4.55 (d, J=4.0 Hz, 1H, C₂H), 4.53 (d, J=3.8 Hz, 1H, C₂H), 4.53(d, J=3.7 Hz, 1H, C₂H), 4.50 (d, J=3.8 Hz, 1H, C₂H), 4.49 (d, J=3.8 Hz,1H, C₂H), 4.41 (m, 1H, C_(β)H), 4.35 (dd, J=3.2, 10.2 Hz, 1H, C₄H), 4.33(dd, J=3.2, 10.7 Hz, 1H, C₄H), 4.27 (dd, J=2.9, 9.0 Hz, 1H, C₄H), 4.24(m, 1H, C_(β)H), 4.18 (dd, J=2.8, 10.0 Hz, 1H, C₄H), 4.15 (m, 1H,C_(β)H), 4.13 (d, J=3.2 Hz, 1H, C₃H), 4.13 (dd, J=3.2, 4.6 Hz, 1H, C₄H),4.12 (d, J=3.2 Hz, 1H, C₃H), 4.07 (dd, J=3.0, 9.8 Hz, 1H, C₄H), 3.78 (d,J=2.9 Hz, 1H, C₃H), 3.77 (d, J=2.8 Hz, 1H, C₃H), 3.70 (d, J=3.2, 1H,C₃H), 3.68 (d, J=3.0, 1H, C₃H), 3.64 (s, 3H, —COOMe), 3.40 (s, 3H, OMe),3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.35 (s, 3H,OMe), 3.32 (s, 3H, OMe), 2.83 (dd, J=2.6, 12.9 Hz, 1H, C_(α)H′), 2.77(dd, J=3.0, 12.4 Hz, 1H, C_(α)H′), 2.76 (dd, J=2.0, 12.4 Hz, 1H,C_(α)H′), 2.55 (dd, J=12.3,12.4 Hz, 1H, C_(α)H), 2.45 (dd, J=5.0, 14.1Hz, 1H, C_(α)H), 2.43 (dd, J=*, 13.1 1H, C_(α)H), 2.42 (dd, J=5.0, 12.7Hz, 1H, C_(α)H), 2.34 (dd, J=4.1, 14.1 Hz, 1H, C_(α)H′), 2.28 (dd,J=12.3, 12.9 Hz, 1H, C_(α)H), 2.19 (dd, J=2.6, 13.1 Hz, 1H, C_(α)H′),2.07 (dd, J=2.8, 12.7 Hz, 1H, C_(α)H′), 2.02 (dd, J=12.1, 12.4 Hz, 1H,C_(α)H), 1.47 (s, 3H, Me), 1.45(s, 9H, Boc), 1.45 (s, 3H, Me), 1.45 (s,3H, Me), 1.45 (s, 3H, Me), 1.43 (s, 3H, Me), 1.43 (s, 3H, Me), 1.37 (s,3H, Me), 1.29 (s, 3H, Me), 1.28 (s, 3H, Me), 1.28 (s, 3H, Me), 1.28 (s,3H, Me), 1.26 (s, 3H, Me). FAB MS: 1592.6 (M⁺+H)

[0195] Part 8: Preparation of Octapeptide (Scheme 4; 27)

[0196] Acid 24 (0.15 g, 0.14 mmol) was treated with HOBt (0.022 g, 0.17mmol), EDCI (0.032 g, 0.17 mmol), 25 (prepared by Boc deprotection of 23(0.16 g, 0.14 mmol) with TFA (0.16 mL) in CH₂Cl₂ (1.5 mL) according toGP-4) and DIPEA (0.04 mL, 0.20 mmol) according to GP-9 and purified bycolumn chromatography (60-120 mesh Silica-gel, 2.5% Methanol-CHCl₃) togive 27 (0.112 g, 39%) as a white solid, M.p. 166-169° C.; [α]_(D)+4.851(c 0.35, CHCl₃), IR (KBr): 3383, 2986, 2935, 1718, 1649, 1539, 1376.5,1166, 1081, 1022 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 9.00 (d, J=9.7 Hz, 1H,R₆—NH), 8.692 (d, J=9.7 Hz, 1H, R₄—NH), 8.616 (d, J=9.7 Hz, 1H, R₈—NH),8.124 (d, J=9.1 Hz, 1H, S₅—NH), 7.75 (d, J=9.7 Hz, 1H, S₃—NH), 7.16 (d,J=8.7 Hz, 1H, S₇—NH), 6.66 (d, J=9.7 Hz, 1H, R₂—NH), 6.18 (d, J=8.7 Hz,1H, S₁—NH), 5.94 (d, J=3.8 Hz, 1H, C₁H), 5.89 (d, J=3.7 Hz, 1H, C₁H),5.88 (d, J=4.0 Hz, 1H, C₁H), 5.87 (d, J=3.7 Hz, 1H, C₁H) 5.86 (d, J=3.7Hz, 1H, C₁H), 5.85 (d, J=3.7 Hz, 1H, C₁H), 5.81 (d, J=3.8 Hz, 1H, C₁H),5.79 (d, J=3.8 Hz, 1H, C₁H), 5.06 (m, 1H, C_(β)H), 4.73 (m, 1H, C_(β)H),4.72 (m, 1H, C_(β)H), 4.56 (d, J=3.7 Hz, 1H, C₂H), 4.55 (m, 1H, C_(β)H),4.55 (d, J=3.7 Hz, 1H, C₂H), 4.555 (d, J=4.0 Hz, 1H, C₂H), 4.555 (d,J=3.8 Hz, 1H, C₂H), 4.52 (d, J=3.7 Hz, 1H, C₂H), 4.52 (d, J=3.8 Hz, 1H,C₂H), 4.51 (d, J=3.8 Hz, 1H, C₂H), 4.51 (d, J=3.8 Hz, 1H, C₂H), 4.39 (m,1H, C_(β)H), 4.35 (dd, J=3.2, 10.2 Hz, 1H, C₄H), 4.33 (m, 1H, C_(β)H),4.30 (dd, J=3.2, 10.7 Hz, 1H, C₄H), 4.32 (dd, J=3.0, 9.5 Hz, 1H, C₄H),4.31 (dd, J=3.1, 10.5 Hz, 1H, C₄H), 4.27 (m, 1H, C_(β)H), 4.17 (d, J=3.1Hz,1H, C₃H), 4.15 (dd, J=2.9 , 10.2 Hz, 1H, C₄H), 4.14 (m, 1H, C_(β)H),4.14 (dd, J=3.0, 9.7 Hz, 1H, C₄H), 4.13 (dd, J=3.1, 6.5 Hz, 1H, C₄H),4.17 (d, J=3.2 Hz, 1H, C₃H), 4.11 (d, J=3.1 Hz, 1H, C₃H), 4.10 (d, J=3.1Hz, 1H, C₃H), 4.06 (dd, J=3.1, 11.9 Hz, 1H, C₄H), 3.81 (d, J=3.2 Hz, 1H,C₃H), 3.723 (d, J=3.0 Hz, 1H, C₃H), 3.72 (d, J=2.9 Hz, 1H, C₃H), 3.69(d, J=3.1 Hz, 1H, C₃H), 3.65 (d, J=3.1 Hz, 3H, C₃H), 3.65 (s, 3H,—COOMe), 3.40 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.366(s, 6H, 2-OMe), 3.344 (s, 3H, OMe), 3.34 (s, 3H, OMe), 3.32 (s, 3H,OMe), 2.93(dd, J=2.2, 12.8 Hz, 1H, C_(α)H′), 2.8 (dd, J=1.7, 12.8 Hz,1H, C_(α)H′), 2.768 (dd, J=2.7, 12.9 Hz, 1H, C_(α)H′), 2.74 (dd, J=2.3,12.8 Hz, 1H, C_(α)H′), 2.6 (dd, J=2.4, 12.9 Hz, 1H, C_(α)H′), 2.49 (dd,J=2.4, 12.7 Hz, 1H, C_(α)H′), 2.47 (dd, J=2.7, 12.8 Hz, 1H, C_(α)H),2.45 (dd, J=4.3, 13.8 Hz, 1H, C_(α)H), 2.44 (dd, J=5.4, 12.8 Hz, 1H,C_(α)H), 2.4 (dd, J=5.7, 12.8 Hz, 1H, C_(α)H), 2.33 (dd, J=5.3, 13.8 Hz,1H, C_(α)H′), 2.26 (dd, J=2.3, 12.8 Hz, 1H, C_(α)H), 2.18 (dd, J=2.3,12.8 Hz, 1H, C_(α)H), 2.13 (dd, J=2.4, 12.8 Hz, 1H, C_(α)H′), 2.08 (dd,J=4.3, 12.7 Hz, 1H, C_(α)H′), 2.01 (dd, J=11.7, 12.8 Hz, 1H, C_(α)H),1.47 (s, 6H, 2-Me), 1.45(s, 9H, Boc), 1.42 (s, 3H, Me), 1.41 (s, 3H,Me), 1.36 (s, 6H, 2-Me), 1.30 (s, 6H, 2-Me), 1.284 (s, 3H, Me), 1.28 (s,6H, 2-Me), 1.25 (s, 3H, Me), 1.26 (s, 6H, 2-Me). FAB MS: 2078.8 (M⁺+H)

[0197] Part 9: Preparation of Tripeptide (Scheme 4; 28)

[0198] Acid 22 (0.4 g, 0.66 mmol) was treated with HOBt (0.107 g, 0.8mmol), EDCI (0.152 g, 0.8 mmol), 7 (prepared by Boc deprotection of 5a(0.248 g, 0.66 mmol) with TFA (0.25 mL) in CH₂Cl₂ (2.5 mL) according toGP-4) and DIPEA (0.17 mL, 0.99 mmol) according to GP-6 and purified bycolumn chromatography (60-120 mesh Silica-gel, 70% EtOAc-pet. ether) togive 28 (0.46 g, 81%) as a white solid, M.p. 92-95° C.; [α]_(D)=−41.06(c 0.4, CHCl₃), IR (KBr): 3396, 2985, 2933, 1725, 1669, 1534, 1380,1169, 1074.5, 1004 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.035 (d, J=8.3 Hz,1H, S₃—NH), 7.033 (d, J=8.3 Hz, 1H, R₂—NH), 5.91 (d, J=3.8 Hz, 1H, C₁H),5.90 (d, J=3.8 Hz, 1H, C₁H), 5.89 (d, J=3.8 Hz, 1H, C₁H), 5.42 (d, J=8.2Hz, 1H, S₁—NH), 4.64 (m, 1H, C_(β)H), 4.55 (d, J=3.8 Hz, 1H, C₂H), 4.54(d, J=3.8 Hz, 1H, C₂H), 4.53 (m, 1H, C_(β)H), 4.51 (d, J=3.8 Hz, 1H,C₂H), 4.43 (dd, J=3.2, 7.6 Hz, 1H, C₄H), 4.28 (dd, J=3.2, 7.5 Hz, 1H,C₄H), 4.24 (m,1H, C_(β)H), 4.24 (dd, J=3.2, 6.8 Hz, 1H, C₄H), 3.75 (d,J=3.1 Hz, 1H, C₃H), 3.70 (d, J=3.3 Hz, 1H, C₃H), 3.68 (s, 3H, —COOMe),3.67 (d, J=3.2 Hz, 1H, C₃H), 3.39 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.36(s, 3H, OMe), 2.67 (dd, J=5.1,15.2 Hz, 1H, C_(α)H′), 2.63 (dd,J=6,7,15.2 Hz, 1H, C_(α)H), 2.52 (m, 1H, C_(α)H), 2.52 (m, 1H, C_(α)H′),2.44 (m, 1H, C_(α)H), 2.37 (m, 1H, C_(α)H), 1.49 (s, 3H, Me), 1.47 (s,6H, 2xMe), 1.43 (s, 9H,-Boc), 1.313 (s, 3H, Me), 1.309 (s, 3H, Me),1.307 (s, 3H, Me). FAB MS: 884.3 (M⁺+Na)

EXAMPLE—4

[0199] Part 1: Preparation of Dipeptide (Scheme 5; 29)

[0200] Acid 9 (0.81 g, 2.24 mmol) was treated with HOBt (0.36 g, 2.7mmol), EDCI (0.52 g, 2.7 mmol) and 8 (prepared by debenzylation of 4(0.82 g 2.24 mmol) with 10% Pd—C (0.08 g) according to GP-1) accordingto GP-5 and purified by column chromatography (60-120 mesh Silica-gel,50% EtOAc-pet ether) to give 29 (1.1 g, 79%) as a white solid, M.p.74-77° C.; [α]_(D)=−39.3 (c 0.5, CHCl₃), IR (KBr): 3408, 2994, 2939.5,1718, 1500, 1370, 1161, 1067, 1011 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 6.69(d, J=8.6 Hz, 1H, R₂—NH), 5.88 (d, J=3.9 Hz, 1H, C₁H), 5.84 (d, J=3.8Hz, 1H, C₁H), 5.8 (d, J=9.4 Hz, 1H, R₁—NH), 4.65 (dddd, J=8.6, 7.3, 5.9,5.6 Hz, 1H, C_(β)H), 4.54 (d, J=3.9 Hz, 1H, C₂H), 4.53 (d, J=3.9 Hz, 1H,C₂H), 4.33 (dd, J=3.1, 7.3 Hz, 1H, C₄H), 4.31 (m, 1H, C_(β)H), 4.17 (m,1H, C₄H), 3.73 (d, J=3.1, 1H, C₃H), 3.68 (s, 3H, —COOMe), 3.67 (d,J=2.8, C₃H), 3.41 (s, 3H, OMe), 3.40 (s, 3H, OMe), 2.75 (dd, J=5.9,15.6Hz, 1H, C_(α)H), 2.61 (dd, J=5.6,15.6 Hz, 1H, C_(α)H′), 2.54 (dd, J=4.5,14.8 Hz, C_(α)H), 2.46 (dd, J=4.5, 14.8 Hz, 1H, C_(α)H), 1.47 (s, 3H,Me), 1.46 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.31 (s, 3H, Me), 1.29 (s,3H, Me). FAB MS: 619.3 (M⁺+H)

[0201] Part 2: Boc Deprotectin of Dipetide (Scheme 5; 30)

[0202] Boc deprotection of 29 (0.36 g, 0.58 mmol) with TFA (0.3 mL) inCH₂Cl₂ (3.5 mL) was performed according to GP-4 to give the amine salt30.

[0203] Part 3: Ester Hydrolysis of Dipeptide (Scheme 5; 31)

[0204] Hydrolysis of ester 29 (0.5 g, 0.81 mmol) with 4N NaOH (3.2 mL)in methanol (3.2 mL) was performed according to GP-3 to give 31 (0.45 g,92%) as a solid, M.p. 114-116° C.; [α]_(D)=−27.822 (c 0.5, CHCl₃); IR(KBr): 3392, 2991, 2939, 1721, 1515, 1383, 1257, 1167, 1063, 1014 cm⁻¹;¹H-NMR (500 MHz, CDCl₃) δ 6.55 (d, J=8.6 Hz, 1H, R₂—NH), 5.99 (d, J=9.6Hz, 1H, R₁—NH), 5.88 (d, J=3.9 Hz, 1H, C₁H), 5.84 (d, J=3.8 Hz, 1H,C₁H), 4.77 (dddd, J=8.7, 7.3, 5.9, 5.6 Hz, 1H, C_(β)H), 4.54 (d, J=3.9Hz, 1H, C₂H), 4.53 (d, J=3.9 Hz, 1H, C₂H), 4.35 (m, 1H, C_(β)H), 4.26(dd, J=3.4, 5.8 Hz, 1H, C4H), 4.16 (m, 1H, C₄H), 3.76 (d, J=3.1 Hz, 1H,C₃H), 3.66 (d, J=2.8 Hz, C₃H), 3.41 (s, 3H, OMe), 3.40 (s, 3H, OMe),2.75 (dd, J=5.9,15.6 Hz, 1H, C_(α)H), 2.61 (dd, J=5.6,15.6 Hz, 1H,C_(α)H′), 2.54 (dd, J=4.5, 14.8 Hz, C_(α)H), 2.46 (dd, J=4.5,14.8 Hz,1H, C_(α)H′), 1.47 (s, 3H, Me), 1.46 (s, 3H, Me), 1.43 (s, 9H, -Boc),1.31 (s, 3H, Me), 1.29 (s, 3H, Me). FAB MS; 605.2 (M⁺+H)

[0205] Part 4: Preparation of Tetrapeptide (Scheme 5; 32)

[0206] Acid 31 (0.35 g, 0.58 mmol) was treated with HOBt (0.94 g, 0.69mmol), EDCI (0.13 g, 0.69 mmol), 30 (prepared by Boc deprotection of 29(0.36 g, 0.58 mmol) with TFA (0.3 mL) in CH₂Cl₂ (3.5 mL) according toGP-4) and DIPEA (0.12 mL, 0.87 mmol) according to GP-7 and purified bycolumn chromatography (60-120 mesh Silica-gel, 2.0% Methanol-CHCl₃) togive 32 (0.47 g, 73.5%) as a white solid, M.p. 195-197° C.;[α]_(D)=−28.98 (c 0.5, CHCl₃), IR (KBr): 3394, 3352, 2987, 2935, 1724,1674, 1526, 1373, 1218, 1166, 1082, 1020 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ7.21 (d, J=7.9 Hz, 1H, R₃—NH), 7.11 (d, J=7.9 Hz, 1H, R₂—NH), 7.00 (d,J=7.9 Hz, 1H, R₄—NH), 5.87 (d, J=3.9 Hz, 1H, C₁H), 5.86 (d, J=3.9 Hz,1H, C₁H), 5.86 (d, J=3.9 Hz, 1H, C₁H), 5.85 (d, J=3.9 Hz, 1H, C₁H), 5.82(d, J=6.1 Hz, 1H, R₁—NH), 4.53 (d, J=3.9 Hz, 1H, C₂H), 4.525 (d, J=3.9Hz, 1H, C₂H), 4.52 (d, J=3.9 Hz, 1H, C₂H), 4.51 (d, J=3.9 Hz, 1H, C₂H),4.61 (m, 1H, C_(β)H), 4.51 (m, 1H, C_(β)H), 4.49 (m, 1H, C_(β)H), 4.34(m, 1H, C₄H), 4.32 (m, 1H, C₄H), 4.30 (m, 1H, C_(β)H), 4.30 (m, 1H,C₄H), 4.25 (m, 1H, C₄H), 3.73 (d, J=3.1 Hz, 1H, C₃H), 3.71 (d, J=2.9 Hz,1H, C₃H), 3.70 (d, J=3.0 Hz, 1H, C₃H), 3.70 (d, J=3.1 Hz, 1H, C₃H), 3.68(s, 3H, —COOMe), 3.4 (s,3H,—OMe), 3.394 (s, 3H, OMe), 3.392 (s, 3H,OMe), 3.388 (s, 3H, OMe), 2.75 (dd, J=5.8, 15.6 Hz, 1H, C_(α)H′), 2.67(dd, J=4.2, 15.6 Hz, 1H, C_(α)H), 2.57 (m, 1H, C_(α)H′), 2.54 (m, 1H,C_(α)H′), 2.51 (m, 2H, C_(α)H,H′,), 2.49 (m, 1H, C_(α)H′), 2.48 (m, 1H,C_(α)H), 1.462 (s, 6H, 2-Me), 1.46 (s, 3H, Me),1.45 (s, 3H, Me), 1.43(s, 9H, -Boc), 1.305 (s, 3H, Me), 1.295 (s, 3H, Me), 1.29 (s, 6H, 2-Me).FAB MS: 1105.3 (M⁺+H)

[0207] Part 5: Ester Hydrolysis of Tetrapeptide (Scheme 5; 33)

[0208] Hydrolysis of ester 32 (0.2 g, 0.18 mmol) with 4N NaOH (0.7 mL)in methanol (0.7 mL) was performed according to GP-3 to give 33 (0.17 g,86%) as a solid, M.p. 202-205° C.; [α]_(D)=−27.32 (c 0.51, CHCl₃), IR(KBr): 3348, 3010, 2940, 1678, 1647, 1527, 1380, 1166, 1075, 1018 cm⁻¹;¹H-NMR (500 MHz, CDCl₃) δ 7.21 (d, J=7.9 Hz, 1H, R₃—NH), 7.11 (d, J=7.9Hz, 1H, R₂—NH), 7.00 (d, J=7.9 Hz, 1H, R₄—NH), 5.92(d, J=3.9 Hz, 1H,C₁H), 5.895 (d, J=3.9 Hz, 1H, C₁H), 5.89 (d, J=3.9 Hz, 1H, C₁H), 5.88(d, J=3.9 Hz, 1H, C₁H), 5.82 (d, J=6.1 Hz,1H, R₁—NH), 4.59 (m, 1H,C_(β)H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.56(d, J=3.9 Hz,1H, C₂H), 4.56(d, J=3.9 Hz, 1H, C₂H), 4.61 (m, 1H, C_(β)H),4.51 (m, 1H, C_(β)H), 4.49 (m, 1H, C_(β)H), 4.34 (m, 1H, C₄H), 4.32 (m,1H, C₄H), 4.30 (m, 1H, C_(β)H), 4.30 (m, 1H, C₄H), 4.25 (m, 1H, C₄H),3.73 (d, J=3.1 Hz, 1H, C₃H), 3.71 (d, J=2.9 Hz, 1H, C₃H), 3.70 (d, J=3.0Hz, 1H, C₃H), 3.70 (d, J=3.1 Hz, 1H, C₃H), 3.394 (s, 3H, OMe), 3.392 (s,3H, OMe), 3.388 (s, 3H, OMe), 3.34 (s, 3H, OMe), 2.73 (dd, J=5.8, 15.6Hz, 1H, C_(α)H′), 2.67 (dd, J=5.8, 15.6 Hz, 1H, C_(α)H), 2.57 (m, 1H,C_(α)H′), 2.54 (m, 1H, C_(α)H′), 2.51 (m, 2H, C_(α)H,H′,), 2.49 (m, 1H,C_(α)H′), 2.48 (m, 1H, C_(α)H), 1.462 (s, 6H, 2-Me), 1.46 (s, 3H,Me),1.45 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.305 (s, 3H, Me), 1.295 (s,3H, Me), 1.29 (s, 6H, 2-Me).

[0209] Part 6: Preparation of Hexapeptide (Scheme 5; 34)

[0210] Acid 33 (0.125 g, 0.115 mmol) was treated with HOBt(0.019 g, 0.14mmol), EDCI (0.027 g, 0.14 mmol), 30 prepared by Boc deprotection of 29(0.071 g, 0.115 mmol) with TFA (0.7 mL) in CH₂Cl₂ (1 mL) as described inGP-4) and DIPEA (0.03 mL, 0.17 mmol) according to GP-8 and purified bycolumn chromatography (60-120 mesh Silica gel, 2.5% Methanol-CHCl₃) togive 34 (0.094 g, 51.5%) as a white solid, M.p. 224-227° C.;[α]_(D)=−32.723 (c 0.75, CHCl₃), IR (KBr): 3348, 2988, 2935, 1724, 1651,1525, 1373, 1217.5, 1166, 1082, 1020 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ7.56 (d, J=8.9 Hz, 1H, R₄—NH), 7.54 (d, J=8.9 Hz, 1H, R₂—NH), 7.34 (d,J=8.9 Hz, 1H, R₅—NH), 7.18 (d, J=9.1 Hz, 1H, R₃—NH), 7.08 (d, J=9.2 Hz,1H, R₆—NH), 5.92 (d, J=3.9 Hz, 1H, C₁H), 5.78 (d, J=3.9 Hz, 1H, C₁H),5.89 (d, J=3.9 Hz, 1H, C₁H), 5.88 (d, J=3.9 Hz, 1H, C₁H), 5.78 (d, J=9.3Hz, 1H, R₁—NH), 4.60 (m, 1H, C_(β)H), 4.47 (m, 1H, C_(β)H), 4.46 (m, 1H,C_(β)H), 4.40 (m, 1H, C_(β)H), 4.39 (m, 1H, C_(β)H), 4.56(d, J=3.9Hz,1H, C₂H), 4.51 (d, J=3.9 Hz, 1H, C₂H), 4.49 (d, J=3.8 Hz, 1H, C₂H),4.34 (m, 1H, C₄H), 4.33 (m, 1H, C₄H), 4.33 (m,1H, C_(β)H), 4.32 (m, 1H,C₄H),4.31(m, 1H, C₄H), 3.75 (d, J=3.1 Hz, 1H, C₃H), 3.73 (d, J=3.1 Hz,1H, C₃H), 3.69 (m, 3H, 3-H3), 3.68 (s, 3H, —COOMe), 3.70 (d, J=3.1 Hz,1H, C₃H), 3.394 (s, 3H, OMe), 3.392 (s, 3H, OMe), 3.388 (s, 3H, OMe),3.34 (s, 3H, OMe), 2.73 (dd, J=5.8, 15.6 Hz, 1H, C_(α)H′), 2.67 (dd,J=5.8,15.6 Hz, 1H, C_(α)H), 2.57 (m, 1H, C_(α)H′), 2.54 (m, 1H, C_(α)H),2.51 (m, 2H, C_(α)H, H′), 2.49 (m,1H, C_(α)H′), 2.48 (m,1H, C_(α)H),1.462 (s, 3H, Me), 1.46 (s, 3H, Me),1.45 (s, 3H, Me), 1.43 (s, 9H,-Boc), 1.305 (s, 3H, Me), 1.295 (s, 3H, Me), 1.29 (s, 6H, 2-Me). FAB MS:1592.3 (M⁺+H)

EXAMPLE—5

[0211] Part 1: Preparation of Dipeptide (Scheme 6; 35)

[0212] Acid 9 (1.65 g, 4.57 mmol) was treated with HOBt (0.74 g, 5.48mmol), EDCI (1.05 g, 5.48 mmol) and 5 (prepared by debenzylation of 3(1.67 g 4.57 mmol) with 10% Pd—C (0.16 g) according to GP-1) accordingto GP-5 and purified by column chromatography (60-120 mesh Silica-gel,50% EtOAc-pet ether) to give 35 (2.24 g, 79%) as a white solid, M.p.157-160° C.; [α]_(D)=−40.763 (c 0.49,CHCl3), IR (KBr): 3335, 3269, 2991,2938, 1730, 1700, 1650, 1526, 1167, 1074, 1013 cm⁻¹; ¹H-NMR (500 MHz,CDCl₃) δ 6.48 (d, J=8.3 Hz, 1H, S₂—NH), 5.68 (d, J=8.7 Hz, 1H, R₁—NH),5.91 (d, J=3.9 Hz, 1H, C₁H), 5.87 (d, J=3.9 Hz, 1H, C₁H), 4.59 (m, 1H,C_(β)H), 4.55 (d, J=3.9 Hz, 1H, C₂H), 4.53 (d, J=3.9Hz, 1H, C₂H), 4.37(m, 1H, C₄H), 4.26 (m, 1H, C_(β)H), 4.25 (m, 1H, C₄H), 3.74 (d, J=3.3,1H, C₃H), 3.73 (d, J=3.3, 1H, C₃H), 3.67 (s, 3H, —COOMe), 3.40 (s, 3H,OMe), 3.38 (s, 3H, OMe), 2.71 (dd, 1H, J=6.4, 14.6, C_(α)H′), 2.62 (dd,J=5.9, 14.6, 1H, C_(α)), 2.57 (dd, J=5.2, 15.3, 1H, C_(α)H′), 2.50 (dd,J=4.2, 15.3, C_(α)H), 1.48 (s, 3H, Me), 1.46 (s, 3H, Me), 1.43 (s, 9H,-Boc), 1.31 (s, 3H, Me), 1.30 (s, 3H, Me). FAB MS: 619.1 (M⁺+H)

[0213] Part 2: Boc Deprotectin of Dipetide (Scheme 6; 36)

[0214] Boc deprotection of 35 (0.92 g, 1.4 mmol) with TFA (1.4 mL) inCH₂Cl₂ (14 mL) was performed according to GP-4 to give the amine salt36.

[0215] Part 3: Ester Hydrolysis of Dipeptide (Scheme 6; 37)

[0216] Hydrolysis of ester 35 (1.05 g, 1.7 mmol) with 4N NaOH (6.7 mL)in methanol (6.7 mL) was performed according to GP-3 to give 37 (0.96 g,92%) as a solid, M.p. 93-95° C.; [α]_(D)=−49.569 (c 0.39, CHCl₃), IR(KBr): 3361.5, 2992, 2939, 1707, 1506, 1354, 1159, 1074, 1008 cm⁻¹;¹H-NMR (500 MHz, CDCl₃) δ 6.91 (d, J=7.0 Hz, 1H, S₂—NH), 5.53 (d, J=8.8Hz, 1H, R₁—NH), 5.90 (d, J=3.9 Hz, 1H, C₁H), 5.89 (d, J=3.9 Hz, 1H,C₁H), 4.59 (d, J=3.9 Hz, 1H, C₂H), 4.55 (d, J=3.9 Hz, 1H, C₂H), 4.34 (m,1H, C_(β)H), 4.33 (m, 1H, C₄H), 4.32 (m, 1H, C_(β)H), 4.18 (d, J=3.1,1H, C₄H), 3.80 (d, J=3.1, 1H, C₃H), 3.75 (d, J=3.1, 1H, C₃H), 3.41(s,3H, OMe), 3,38 (s, 3H, OMe), 2.64 (m, 2H, C_(α)H,H′), 2.60 (dd,J=3.8,15.1, 1H, C_(α)H′), 2.48 (dd, J=7.8, 15.1, C_(α)H), 1.50 (s, 3H,Me), 1.47 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.32 (s, 3H, Me), 1.31 (s,3H, Me). FAB MS: 605.2 (M⁺+H)

[0217] Part 4: Preparation of Tetrapeptide (Scheme 6; 38)

[0218] Acid 37 (0.98 g, 1.5 mmol) was treated with HOBt (0.24 g, 1.8mmol), EDCI (0.34 g, 1.8 mmol), 36 prepared by Boc deprotection of 35(0.92 g, 1.5 mmol) with TFA (0.9 mL) in CH₂Cl₂ (9 mL) according to GP-4)and DIPEA (0.4 mL, 2.23 mmol) according to GP-7 and purified by columnchromatography (60-120 mesh Silica-gel, 2% Methanol-CHCl₃) to give 38(1.36 g, 82.7%) as a white solid, M.p. 126-128° C.; [α]_(D)=−2.96 (c0.54, CHCl3), IR (KBr): 3367, 2987, 2937, 1735, 1668, 1526, 1375, 1217,1166, 1081, 1021 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.89 (d, J=9.6 Hz, 1H,R₃—NH), 7.46 (d, J=8.5 Hz, 1H, S₂—NH), 6.68 (d, J=8.2 Hz, 1H, S₄—NH),6.04 (d, J=3.9 Hz, 1H, C₁H), 5.98 (d, J=4.0 Hz, 1H, C₁H), 5.87 (d, J=3.9Hz, 1H, C₁H), 5.86 (d, J=3.9 Hz, 1H, C₁H), 5.10 (d, J=10.6 Hz, 1H,R₁—NH), 4.72 (m, 1H, C_(β)H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.55 (d,J=3.9 Hz, 1H, C₂H), 4.53 (d, J=4.0 Hz, 1H, C₂H), 4.51 (d, J=3.9 Hz, 1H,C₂H), 4.47 (m, 1H, C_(β)H), 4.46 (m, 1H, C₄H), 4.41 (m, 1H, C_(β)H),4.40 (m, 1H, C_(β)H), 4.31 (dd, J=3.3, 9.8 Hz, 1H, C₄H), 4.16 (dd,J=3.2, 9.3 Hz, 1H, C₄H), 4.14 (d, J=3.3 Hz, 1H, C₃H), 3.96 (dd, J=3.2,8.2 Hz, 1H, C₄H), 3.69 (d, J=3.2 Hz, 1H, C₃H), 3.68 (d, J=3.2 Hz, 1H,C₃H), 3.67 (d, J=3.2 Hz, 1H, C₃H), 3.67(s, 3H, —COOMe), 3.37 (s, 3H,OMe), 3.35 (s, 3H, OMe), 3.34 (s, 3H, OMe), 3.33 (s, 3H, OMe), 2.97 (dd,J=2.9, 13.0 Hz, 1H, C_(α)H′), 2.77 (dd, J=4.4, 15.5 Hz, 1H, C_(α)H),2.67 (dd, J=2.8, 14.8 Hz, 1H, C_(α)H′), 2.50 (dd, J=5.2, 15.5 Hz, 1H,C_(α)H′), 2.47 (dd, J=10.5, 14.8 Hz, 1H, C_(α)H), 2.42 (dd, J=4.7, 13.2Hz, 1H, C_(α)H), 2.18 (dd, J=2.6, 13.2 Hz, 1H, C_(α)H′), 2.04 (dd,J=13.0, 13.0 Hz, 1H, C_(α)H), 1.48 (s, 3H, Me), 1.47 (s, 3H, Me), 1.43(s, 9H, Boc), 1.43 (s, 3H, Me), 1.43 (s, 3H, Me), 1.38 (s, 3H, Me), 1.30(s, 3H, Me), 1.29 (s, 3H, Me), 1.28 (s, 3H, Me). FAB MS: 1105.4 (M⁺+H)

[0219] Part 5: Ester Hydrolysis of Tetrapeptide (Scheme 6; 39)

[0220] Hydrolysis of Ester 38 (1.05 g, 0.95 mmol) with 4N NaOH (4 mL) inmethanol (4 mL) was performed according to GP-3 to give 39 (0.93 g, 90%)as a solid, M.p. 144-147 ° C.; [α]_(D)=+8.3868 (c 0.57, CHCl₃), IR(KBr): 3324, 2983, 2929, 1685, 1659, 1531, 1375, 1215, 1164, 1070, 1012cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 8.49 (d, J=9.5 Hz, 1H, R₃—NH), 7.85 (d,J=Hz, 1H, S₂—NH), 6.35 (d, J=9.3 Hz, 1H S₄—NH), 5.91(d, J=3.9 Hz, 1H,C₁H), 5.90(d, J=3.9 Hz, 1H, C₁H), 5.89 (d, J=3.9 Hz, 1H, C₁H), 5.87 (d,J=3.9 Hz, 1H, C₁H), 5.34 (d, J=10.3 Hz, 1H, R₁—NH), 4.59 (d, J=3.9 Hz,1H, C₂H), 4.55 (d, J=3.9 Hz, 1H, C₂H), 4.49 (m, 1H, C_(β)H), 4.47 (m,1H, C_(β)H), 4.45(m, 1H, C₄H), 4.40 (m, 1H, C_(β)H), 4.38 (m, 1H,C_(β)H), 4.36 (m, 1H, C₄H), 4.21 (m, 1H, C₄H), 4.09 (m, 1H, C₃H), 3.95(m, 1H, C₄H), 3.94 (d, J=3.1 Hz, 1H, C₃H), 3.69 (d, J=3.0 Hz, 1H C₃H),3.65 (d, J=3.1 Hz, 1H, C₃H), 3.39 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.35(s, 3H, OMe), 3.34 (s, 3H, OMe), 2.88 (m, 1H, C_(α)H′), 2.81 (dd, J=*,1H, C_(α)H′), 2.70 (dd, J=*, C_(α)H′), 2.42 (dd, J=, C_(α)H), 2.39 (dd,J=, C_(α)H), 2.37 (dd, J=, C_(α)H′), 2.26 (dd, J=, C_(α)H), 2.14 (dd,J=, C_(α)H), 1.50 (s, 3H, Me), 1.49 (s, 3H, Me), 1.44 (s, 3H, Me), 1.43(s, 9H, -Boc), 1.37 (s, 3H, Me), 1.32 (s, 3H, Me), 1.31 (s, 6H, 2-Me),1.29 (s, 3H, Me). FAB MS: 1091.2 (M⁺+H)

[0221] Part 6: Boc Deprotectin of Tetrapetide (Scheme 6; 40)

[0222] Boc deprotection of 39 (0.061 g, 0.055 mmol) with TFA (0.1 mL) inCH₂Cl₂ (1 mL) according to GP-4 gave 40.

[0223] Part 7: Preparation of Hexapeptide (Scheme 6; 41)

[0224] Acid 39 (0.3 g, 0.28mmol) was treated with HOBt (0.045 g, 0.33mmol), EDCI (0.063 g, 0.33 mmol), 36 (prepared by Boc deprotection of 35(0.17 g, 0.28 mmol) with TFA (0.2 mL) in CH₂C₂ (2 mL) as described inGP-4) and DIPEA (0.07 mL, 0.4 mmol) according to GP-8 and purified bycolumn chromatography (60-120 mesh Silica gel, 2.5% Methanol-CHCl₃) togive 41 (0.265 g, 60%) as a white solid, M.p. 164-167° C.;[α]_(D)=+26.658 (c 0.29, CHCl₃), IR (KBr): 3291, 2987.5, 2937, 1734,1652.5, 1542, 1376, 1217, 1165.5, 1081.5, 1021 cm⁻¹; ¹H-NMR (500 MHz,CDCl₃) δ 8.61 (d, J=9.9 Hz, 1H, R₃—NH), 8.46 (d, J=9.7 Hz, 1H, R₅—NH)8.23 (d, J=10.0 Hz, 1H, S₂—NH), 7.41 (d, J=7.3 Hz, 1H, S₄—NH), 6.85 (d,J=8.2 Hz, 1H, S₆—NH), 6.20 (d, J=3.7 Hz, 1H, C₁H), 6.12 (d, J=3.8 Hz,1H, C₁H), 5.88 (d, J=3.6 Hz, 1H, C₁H), 5.87 (d, J=3.9 Hz, 1H, C₁H), 5.86(d, J=4.1 Hz, 1H, C₁H), 5.81 (d, J=3.8 Hz, 1H, C₁H), 5.47 (d, J=10.6 Hz,1H, R₁—NH), 4.81 (m, 1H, C_(β)H), 4.70 (m, 1H, C_(β)H), 4.61 (d, J=3.6Hz, 1H, C₂H), 4.57 (d, J=3.7 Hz, 1H, C₂H), 4.56 (m, 1H, C_(β)OH), 4.56(d, J=3.8 Hz, 1H, C₂H), 4.55 (d, J=4.1 Hz, 1H C₂H), 4.54 (d, J=3.8 Hz,1H, C₂H), 4.53 (m, 1H, C_(β)H), 4.47 (d, J=3.9 Hz, 1H, C₂H1), 4.42 (m,1H, C_(β)H), 4.38 (dd, J=3.2, 9.4 Hz, 1H, C₄H), 4.36 (m, 1H, C_(β)H),4.36 (m, 1H, C₄H), 4.34 (dd, J=3.1, 10.2 Hz, 1H, C₄H), 4.19(d, J=3.2 Hz,1H, C₃H), 4.17 (dd, J=3.0, 9.7 Hz, 1H, C₄H), 4.17 (d, J=3.2 Hz, 1H,C₃H), 4.10 (dd, J=3.1, 9.9 Hz, 1H, C₄H), 4.06 (dd, J=3.4, 6.0 Hz, 1H,C₄H), 3.76 (d, J=3.0 Hz, 1H, C₃H), 3.68 (d, J=3.1 Hz, 1H, C₃H), 3.66 (s,3H, —COOMe), 3.67 (d, J=3.4 Hz, 1H, C₃H), 3.62 (d, J=3.1 Hz, 1H, C₃H),3.41 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.32 (s, 3H,OMe), 3.32 (s, 3H, OMe), 3.30 (s, 3H, OMe), 3.13 (dd, J=2.1, 12.8 Hz,1H, C_(α)H′), 2.82 (dd, J=4.6, 15.4 Hz, 1H, C_(α)H), 2.77 (dd, J=2.6,12.5 Hz, 1H, C_(α)H′), 2.68 (dd, J=2.4, 15.2 Hz, 1H, C_(α)H′), 2.53 (dd,J=11.8, 15.2 Hz, 1H, C_(α)H), 2.52 (dd, J=5.4, 12.8 Hz, 1H, C_(α)H),2.50 (dd, J=5.5, 15.4 Hz, 1H, C_(α)H′), 2.29 (dd, J=5.0, 12.8 Hz, 1H,C_(α)H), 2.25 (dd, J=3.2, 12.8 Hz, 1H, C_(α)H′), 2.20 (t, J=12.8 Hz, 1H,C_(α)H), 2.11 (t, J=12.5 Hz, 1H, C_(α)H), 2.05 (dd, J=2.7, 12.8 Hz, 1HC_(α)H′), 1.50 (s, 3H, Me), 1.46 (s, 3H, Me), 1.45 (s, 3H, Me), 1.44 (s,3H, Me), 1.42 (s, 9H, Boc), 1.36 (s, 3H, Me), 1.33 (s, 3H, Me), 1.31 (s,3H, Me), 1.28 (s, 3H, Me), 1.28 (s, 3H, Me), 1.28 (s, 3H, Me), 1.27 (s,3H, Me), 1.26 (s, 3H, Me). FAB MS: 1592.5 (M⁺+H)

[0225] Part 8: Preparation of Octapeptide (Scheme 6; 42)

[0226] Acid 39 (0.06 g, 0.055 mmol) was treated with HOBt (0.009 g, 0.07mmol), EDCI (0.013 g, 0.07 mmol), 40 (prepared by Boc deprotection of 38(0.061 g, 0.055 mmol) with TFA (0.1 mL) in CH₂C₂ (1 mL) according toGP-4) and DIPEA (0.015 mL, 0.08 mmol) according to GP-9 and purified bycolumn chromatography (60-120 mesh Silica-gel, 3% Methanol-CHCl₃) togive 42 (0.051 g, 45%) as a white solid, M.p. 164-167° C.;[α]_(D)=+19.581(c 0.23, CHCl₃), IR (KBr): 3283, 2988, 2935, 1648, 1560,1376, 1214, 1166, 1081, 1022cm⁻¹; ¹H-NMR(500 MHz, CDCl₃) δ 8.92 (d,J=10.1 Hz, 1H, R₅—NH), 8.60 (d, J=10.1 Hz, 1H, R₃—NH), 8.596 (d, J=10.0Hz, 1H, R₇—NH), 8.29 (d, J=9.3 Hz, 1H, S₄—NH), 7.94 (d, J=10.2 Hz, 1H,S₂—NH), 7.42 (d, J=8.2 Hz, 1H, S₆—NH), 6.88(d, J=8.2 Hz, 1H S₈—NH),6.12(d, J=3.7 Hz, 1H, C₁H), 6.08 (d, J=3.8 Hz, 1H, C₁H), 5.89 (d, J=3.6Hz, 1H, C₁H), 5.89 (d, J=3.6 Hz, 1H, C₁H), 5.88 (d, J=3.9 Hz, 1H, C₁H),5.87 (d, J=4.1 Hz, 1H, C₁H), 5.87 (d, J=4.1 Hz, 1H, C₁H), 5.82 (d, J=3.8Hz, 1H, C₁H), 5.35 (d, J=8.5 Hz, 1H, R₁—NH), 4.77 (m, 1H, C_(β)H), 4.75(m, 1H, C_(β)H), 4.66 (m, 1H, C_(β)H), 4.58 (d, J=3.8 Hz, 1H, C₂H), 4.57(d, J=3.7 Hz, 1H, C₂H), 4.57 (d, J=3.7 Hz, 1H, C₂H), 4.56 (d, J=3.9 Hz,1H, C₂H), 4.55 (d, J=3.8 Hz, 1H, C₂H), 4.55 (d, J=3.8 Hz, 1H, C₂H), 4.51(m, 1H, C_(β)H), 4.51 (d, J=3.8 Hz, 1H, C₂H), 4.50 (m, 1H, C_(β)H), 4.44(m, 1H, C_(β)H), 4.43 (d, J=3.8 Hz, 1H, C₂H), 4.42 (dd, J=3.2, 9.4 Hz,1H, C₄H), 4.38(m, 1H, C_(β)H), 4.36 (m, 1H, C_(β)H), 4.33 (dd, J=3.1,9.4 Hz, 1H, C₄H), 4.30 (dd, J=3.2, 9.7 Hz, 1H, C₄H), 4.22 (m, 1H, C₄H),4.16 (dd, J=3.2, 9.6 Hz, 1H, C₄H), 4.16 (dd, J=3.1, 9.7 Hz, 1H, C₄H),4.15(d, J=3.2 Hz, 1H, C₃H), 4.12 (d, J=3.2 Hz, 1H, C₃H), 4.10 (dd,J=3.1, 10.0 Hz, 1H, C₄H), 4.04 (dd, J=3.2, 6.7 Hz, 1H, C₄H), 3.73 (d,J=3.0 Hz, 1H, C₃H), 3.73 (d, J=3.0 Hz, 1H, C₃H), 3.67 (s, 3H, —COOMe),3.66 (d, J=3.2 Hz, 1H, C₃H), 3.65 (d, J=3.1 Hz, 1H, C₃H), 3.61 (d, J=3.1Hz, 1H, C₃H), 3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.37 (s, 3H, OMe),3.36 (s, 3H, OMe), 3.35 (s, 3H, OMe), 3.34(s, 3H, OMe), 3.33 (s, 3H,OMe), 3.25 (s, 3H, OMe), 2.97 (dd, J=1.5, 12.8 Hz, 1H, C_(α)H′), 2.89(dd, J=2.2, 12.8 Hz, 1H, C_(α)H), 2.88 (dd, J=2.2, 12.2 Hz, 1H, C_(α)H),2.81(m,1H, C_(α)H′), 2.67 (dd, J=1.9, 12.1 Hz, 1H, C_(α)H′), 2.56 (dd,J=11.8, 15.2 Hz, 1H, C_(α)H), 2.55 (dd, J=5.4, 12.8 Hz, 1H, C_(α)H),2.48 (dd, J=5.5, 15.4 Hz, 1H, C_(α)H′), 2.42 (dd, J=5.5, 154 Hz, 1H,C_(α)H), 2.36 (dd, J=5.0, 12.8 Hz, 1H, C_(α)H), 2.32 (dd, J=3.2, 12.8Hz, 1H, C_(α)H′), 2.28 (t, J=12.8 Hz, 1H, C_(α)H), 2.26 (t, J=12.5 Hz,1H, C_(α)H), 2.16 (dd, J=2.7, 15.4 Hz, 1H, C_(α)H′), 2.09 (dd, J=2.7,12.8 Hz, 1H, C_(α)H′), 2.05 (dd, J=2.7, 12.8 Hz, 1H, C_(α)H), 1.50 (s,3H, Me), 1.46 (s, 3H, Me), 1.45 (s, 3H, Me), 1.44 (s, 3H, Me), 1.42 (s,9H, Boc), 1.36 (s, 3H, Me), 1.33 (s, 3H, Me), 1.31 (s, 3H, Me), 1.28 (s,3H, Me), 1.28 (s, 3H, Me), 1.28 (s, 3H, Me), 1.27 (s, 3H, Me), 1.26 (s,3H, Me). FAB MS: 2078.4 (M⁺+H)

[0227] Part 9: Preparation of Tripeptide (Scheme 6; 43)

[0228] Acid 37 (0. 15 g, 0.25 mmol) was treated with HOBt (0.04 g, 0.3mmol), EDCI (0.06 g, 0.3 mmol), 10 (prepared by Boc deprotection of 8a(0.094 g, 0.25 mmol) with TFA (0.1 mL) in CH₂C₂ (1.0 mL) according toGP-4) and DIPEA (0.06 mL, 0.37 mmol) according to GP-6 and purified bycolumn chromatography (60-120 mesh Silica-gel, 70% EtOAc-pet. ether) togive 43 (0.16 g, 75.1%) as a white solid, M.p. 108-111° C.;[α]_(D)=−5.103 (c 0.45, CHCl₃), IR (KBr): 3364, 3308, 2996, 2940, 1717,1670, 1542, 1371, 1164, 1077, 1010 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 8.08(d, J=9.5 Hz, 1H, R₃—NH), 7.19 (d, J=9.6 Hz, 1H, S₂—NH), 5.89 (d, J=3.8Hz, 1H, C₁H), 5.89 (d, J=3.8 Hz, 1H, C₁H), 5.85 (d, J=3.8 Hz, 1H, C₁H),5.26 (d, J=10.5 Hz, 1H, R₁—NH), 4.69 (m, 1H, C_(β)H), 4.57 (d, J=3.8 Hz,1H, C₂H), 4.53 (d, J=3.8 Hz, 1H, C₂H), 4.53 (m, 1H, C_(β)H), 4.52 (d,J=3.8 Hz, 1H, C₂H), 4.50 (m,1H C_(β)H), 4.30 (dd, J=7.6, 3.2 Hz, 1H,C₄H), 4.17 (dd, J=7.5, 3.2 Hz, 1H, C₄H), 4.13 (d, J=3.1 Hz, 1H, C₃H),3.99 (dd, J=6.8,3.2 Hz, 1H, C₄H), 3.71 (d, J=3.3 Hz, 1H, C₃H), 3.70 (d,J=3.2 Hz, 1H C₃H), 3.66 (s, 3H, COOMe), 3.39(s, 3H, OMe), 3.38 (s, 3H,OMe), 3.36(s, 3H, OMe), 2.78 (dd, J=2.7,12.4 Hz, 1H, C_(α)H′), 2.53 (m,2H, C_(α)H,H′), 2.34 (dd, J=4.9,13.1 Hz, 1H C_(α)H), 2.22 (dd, J=3.3,13.1, 1H, C_(α)H′), 2.16 (dd, J=12.4,12.9 Hz, 1H, C_(α)H′), 1.44 (s, 6H,2X Me), 1.43 (s, 9H, -Boc), 1.39 (s, 3H, Me), 1.306 (s, 3H, Me), 1.298(s, 3H, Me), 1.29 (s, 3H, Me).

EXAMPLE—6

[0229] Part 1: Preparation of Tetrapeptide (Scheme 7; 44)

[0230] Acid 22 (0.1 g, 0.165 mmol) was treated with HOBt (0.027 g, 0.2mmol), EDCI (0.038 g, 0.2 mmol), 36 (prepared by Boc deprotection of 35(0.105 g, 0.165 mmol) with TFA (0.1 mL) in CH₂Cl₂ (1 mL) according toGP-4) and DIPEA (0.065 mL, 0.25 mmol) according to GP-7 and purified bycolumn chromatography (60-120 mesh Silica-gel, 2% Methanol-CHCl₃) togive 44 (0.135 g, 73.9%) as a white solid, M.p. 112-115° C.;[α]_(D)=−43.619 (c 0.36, CHCl₃), IR (KBr): 3388, 2988, 2941, 1718, 1675,1521, 1368, 1164, 1070, 1021 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.24 (d,J=9.3 Hz, 1H, R2-NH), 7.07 (d, J=9.3 Hz, 1H, R3-NH), 6.95 (d, J=8.4 Hz,1H, S4-NH), 5.88 (d, J=3.9 Hz, 1H, C₁H), 5.88 (d, J=4.0 Hz, 1H C_(α)H),5.90 (d, J=3.9 Hz, 1H, C₁H), 5.87 (d, J=3.9 Hz, 1H, C₁H), 5.54 (d, J=9.7Hz, 1H, S1-NH), 4.64 (m, 1H, C_(β)H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.55(m, 1H, C_(β)H), 4.55 (d, J=3.9 Hz, 1H, C₂H), 4.53 (d, J=4.0 Hz, 1H,C₂H), 4.53 (d, J=3.9 Hz, 1H, C₂H), 4.49 (m, 1H, C_(β)H), 4.42 (dd,J=3.2, 8.1 Hz, 1H, C₄H), 4.31 (dd, J=3.3, 7.6 Hz, 1H, C₄H), 4.30 (dd,J=3.2, 7.8 Hz, 1H, C₄H), 4.24 (m, 1H, C_(β)H), 4.21 (dd, J=3.2, 7.9 Hz,1H, C4H), 3.74 (d, J=3.3 Hz, 1H, C₃H), 3.67 (d, J=3.0 Hz, 1H, C₃H), 3.68(s, 3H, —COOMe), 3.67 (d, J=3.2 Hz, 1H, C₃H), 3.64 (d, J=3.2 Hz, 1H,C₃H), 3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.36 (s,3H, OMe), 2.66 (d, J=6.0 Hz, 2H, C_(α)H,H′), 2.57 (dd, J=5.4, 14.5 Hz,1H, C_(α)H), 2.55 (m, 1H C_(α)H), 2.53 (m, 1H, C_(α)H), 2.47 (m, 1H,C_(α)H), 2.44 (dd, J=4.2, 14.5 Hz, 1H C_(α)H), 2.44 (m, 1H, C_(α)H′),1.47 (s, 3H, Me), 1.45 (s, 3H, Me), 1.446 (s, 6H, 2-Me), 1.446 (s, 311,Me), 1.42 (s, 9H, Boc), 1.31 (s, 3H, Me), 1.30 (s, 3H, Me), 1.29 (s, 3H,Me). FAB MS: 1105.2 (M⁺+H)

[0231] Part 2: Preparation of Tetrapeptide (Scheme 7; 45)

[0232] Acid 37 (0.07 g, 0.116 mmol) was treated with HOBt (0.02 g, 0.14mmol), EDCI (0.027 g, 0.14 mmol), 21 (prepared by Boc deprotection of 20(0.072 g, 0.125 mmol) with TFA (0.1 mL) in CH₂Cl₂ (1 mL) according toGP-4) and DIPEA (0.03 mL, 0.17 mmol) according to GP-7 and purified bycolumn chromatography (60-120 mesh Silica-gel, 2% Methanol-CHCl₃) togive 45 (0.102 g, 79.7%) as a white solid, M.p. 118-121° C.;[α]_(D)=−26.569 (c 0.5, CHCl3), IR (KBr): 3387, 2987, 2940, 1724, 1662,1538, 1377, 1158, 1080, 1013 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 7.29 (d,J=9.0 Hz, 1H, S3-NH), 7.05 (d, J=9.1 Hz, 1H, R4-NH), 6.84 (d, J=8.9 Hz,1H, S2-NH), 5.90 (d, J=4.0 Hz, 1H, C₁H), 5.88 (d, J=3.9 Hz, 1H, C₁H),5.88 (d, J=3.9 Hz, 1H, C₁H), 5.87 (d, J=3.9 Hz, 1H, C₁H), 5.63 (d, J=9.8Hz, 1H, R1-NH), 4.65 (m, 1H, C_(β)H), 4.57 (d, J=3.9 Hz, 1H, C₂H), 4.55(d, J=3.9 Hz, 1H, C₂H), 4.53 (d., J=4.0 Hz, 1H, C₂H), 4.53 (d, J=3.9 Hz,1H, C₂H), 4.52 (m, 1H, C_(β)H), 4.48 (m, 1H, C_(β)H), 4.36 (m, 1H,C_(β)H), 4.34 (dd, J=3.3, 7.7 Hz, 1H, C₄H), 4.28 (dd, J=3.2, 7.3 Hz, 1H,C₄H), 4.22 (dd, J=3.2, 8.7 Hz, 1H, C₄H), 4.18 (dd, J=3.2, 1.6 Hz, 1H,C₄H), 3.95 (d, J=2.9 Hz, 1H, C₃H), 3.76 (d, J=3.1 Hz, 1H, C₃H), 3.74 (d,J=3.0 Hz, 1H, C₃H), 3.72 (d, J=2.8 Hz, 1H, C₃H), 3.68 (s, 3H, —COOMe),3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.36 (s, 3H,OMe), 2.69 (dd, J=4.8, 15.5 Hz, 1H, C_(α)H′), 2.63 (dd, J=7.0, 15.5 Hz,1H, C_(α)H), 2.56 (dd, J=4.2, 14.6 Hz, 1H, C_(α)H′), 2.48 (dd, J=6.5, 15Hz, 1H, C_(α)H′), 2.46 (m, 1H, C_(α)H), 2.40 (dd, J=4.8, 15.0 Hz, 1H,C_(α)H), 2.43 (m, 1H, C_(α)H′), 2.43 (m, 1H, C_(α)H), 1.47 (s, 3H, Me),1.45 (s, 3H, Me), 1.42 (s, 9H, Boc), 1.46 (s, 3H, Me), 1.46 (s, 3H, Me),1.31 (s, 3H, Me), 1.30 (s, 3H, Me), 1.29 (s, 3H, Me), 1.29 (s, 3H, Me).FAB MS: 1105.1 (M⁺+H)

EXAMPLE—7

[0233] Part 1: Preparation of Dipeptide (Scheme 8; 47)

[0234] Acid 6 (0.45 g, 1.25 mmol) was treated with HOBt (0.202 g, 1.5mmol), EDCI (0.287 g, 1.5 mmol) and 46 (prepared by neutralization ofβ-alanine methyl ester salt (0.174 g, 4.57 mmol) with DIPEA (0.32 mL,1.87 mmol), according to GP-5 and purified by column chromatography(60-120 mesh Silica-gel, 60% EtOAc-pet ether) to give 47 (0.475 g,85.6%) as a white solid, M.p. 140-142° C.; [α]_(D)=−38.236 (c 0.5,CHCl3), IR (KBr): 3355, 2981, 1744.5, 1693, 1651, 1528, 1370, 1250,1172, 1076, 1022 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ 6.59 (bs, 1H, Ala-NH),5.90 (d, J=3.9 Hz, 1H C₁H), 5.13 (bs, 1H, S1-NH), 4.58 (d, J=3.9 Hz, 1H,C₂H), 4.27 (dd, J=7.7, 3.2, 1H, C₄H), 4.14 (m, 1H, C_(β)H), 3.73 (d,J=3.2, 1H, C₃H), 3.70 (s, 3H, COOMe), 3.51 (q, J=6.1 Hz, 2H, C_(β)H),3.37(s, 3H, OMe), 2.54 (t, J=6.1 Hz, 2H, C_(α)H,H′), 2.52 (dd,J=5.9,14.8, 1H, C_(α)H), 2.46 (dd, J=6.0, 14.8, C_(α)H′), 1.48 (s, 3H,Me), 1.43 (s, 9H, -Boc), 1.32 (s, 3H, Me). FAB MS: 447.2 (M⁺+H)

[0235] Part 2: Boc Deprotectin of Dipetide (Scheme 8; 48)

[0236] Boc deprotection of 47 (0.134 g, 0.30 mmol) with TFA (0.15 mL) inCH₂Cl₂ (1.5 mL) was performed according to GP-4 to give the amine salt48.

[0237] Part 3: Ester Hydrolysis of Dipeptide (Scheme 8; 49)

[0238] Hydrolysis of ester 47 (0.225 g, 0.505 mmol) with 4N NaOH (2 mL)in methanol (2 mL) was performed according to GP-3 to give 49 (0.19 g,88.1%) as a solid, M.p 147-149° C.; [α]_(D)=−41.7555 (c 0.6, CHCl₃), IR(KBr): 3354, 2981, 1692, 1648, 1528, 1370, 1251, 1168, 1076, 1021 cm⁻¹;¹H-NMR (500 MHz, CDCl₃) δ 7.11 (bS, 1H, Ala-NH), 5.90 (d, J=3.9 Hz, 1H,C₁H), 5.23 (bs, 1H, S1-NH), 4.58 (d, J=3.9 Hz, 1H, C₂H), 4.33 (m, 1H,C₄H), 4.15 (m, 1H, C_(β)H), 3.73 (d, J=3.2, 1H, C₃H), 3.52 (m, 2H,C_(β)H), 3.37(s, 3H, OMe), 2.57 (t, J=6.1 Hz, 2H, C_(α)H,H′), 2.49 (m,2H, C_(α)H,H′), 1.48 (s, 3H, Me), 1.43 (s, 9H, -Boc), 1.32 (s, 3H, Me).FAB MS: 433.2 (M⁺+H)

[0239] Part 4: Preparation of Tetrapeptide (Scheme 8; 50)

[0240] Acid 49 (0.13 g, 0.3 mmol) was treated with HOBt (0.05 g, 0.36mmol), EDCI (0.05 g, 0.36 mmol), 48 (prepared by Boc deprotection of 47(0.134 g, 0.3 mmol) with TFA (0.15 mL) in CH₂Cl₂ (1.5 mL) according toGP-4) and DIPEA (0.08 mL, 0.45 mmol) according to GP-7 and purified bycolumn chromatography (60-120 mesh Silica-gel, 3% Methanol-CHCl₃) togive 50 (0.18 g, 78.7%) as a white solid, M.p. 184-186° C.;[α]_(D)=−64.635 (c 0.6, CHCl₃), IR (KBr): 3336, 2984, 2937, 1740, 1690,1654, 1542, 1372, 1254, 1168, 1079, 1020 cm⁻¹; FAB MS: 761.3 (M⁺+H)

[0241] Part 5: Ester Hydrolysis of Tetrapeptide (Scheme 8; 51)

[0242] Hydrolysis of ester 50 (0.5 g, 0.66 mmol) with 4N NaOH (2.5 mL)in methanol (2.5 mL) was performed according to GP-3 to give 51 (0.43 g,87.6%) as a solid, M.p. 165-168° C.; IR (KBr): 3317, 2988, 2941, 1717,1647, 1537, 1364, 1247, 1160, 1074, 1011 cm⁻¹;

[0243] Part 6: Preparation of Hexapeptide (Scheme 8; 52)

[0244] Acid 51 (0.2 g, 0.27 mmol) was treated with HOBt (0.04 g, 0.32mmol), EDCI (0.06 g, 0.32 mmol), 48 (prepared by Boc deprotection of 47(0.12 g, 0.27 mmol) with TFA (0.1 mL) in CH₂Cl₂ (1 mL) as described inGP-4) and DIPEA (0.07 mL, 0.4 mmol) according to GP-8 and purified bycolumn chromatography (60-120 mesh Silica gel, 4% Methanol-CHCl₃) togive 52 (0.155 g, 53.8%) as a white solid, M.p. 220-223° C.; IR (KBr):3301, 2978, 2932, 1656, 1547, 1368, 1173, 1081, 1025 cm⁻¹.

References

[0245] Gellman et al, J. Am. Chem. Soc., 116, 1054-1062 (1994)

[0246] Seabach et al, Helv. Chim. Acta, 79, 913-941 and 2043-2066 (1996)

[0247] Gellman et al, J. Am. Chem. Soc., 118, 13071-72 (1996)

[0248] Gellman et al, Nature, 387, 381 (1997)

[0249] Gellman et al, U.S. Pat. No. 6,060,585 (2000)

[0250] Seebach et al, Helv. Chim. Acta, 81, 932 (1998)

[0251] Seebach et al, Helv. Chim. Acta, 81, 2218-2243 (1998)

[0252] Schweizer, Angew. Chem. Int. E., 41, 230-253 (2002)

[0253] Kessler et al, Chem. Rev., 102, 491-514 (2002)

[0254] Kessler et al, Chem. Eur. J., 8, 4366-4376 (2002)

[0255] Sharma et al, Tetrahedron: Asymm., 13, 21-24, (2002)

[0256] Dhawale et al, J. Org. Chem., 16, 1065, 2001

[0257] Bodanszky et al, The practice of Peptide Synthesis, SpringerVerlag, New York, 1984

[0258] Cavanagh et al, Protein NMR Spectroscopy, Academic Press, SanDiego, 1996

[0259] Wuthrich et al, NMR of Proteins and Nucleic Acids, Wiley, NewYork, 1986

[0260] States et al, J. Magn. Reson. 48, 286-292, 1982

We claim novel nonnatural C-linked carbo-β-peptides with robustsecondary structures, which comprises of the synthesis of a new class ofβ-peptides called C-linked carbo-β-peptides, most of which are favorablydisposed for the formation of stable helical structures:
 1. NovelC-linked β-peptides (oligomers) class of compounds having the generalformula as shown in formula I

n=0, 1, 2, 3 . . . R=H, Boc, Cbz, Fmoc, acetyl or salts such as HCl, TFAand others R=—O alkyl, —O-aralkyl, -amine, alkylamine, aryalkyl maineR²=R³=R⁴=R⁵=H R²=sugar or hydroxy alkyl, amino alkyl/thioalkyl,R³=R⁴=R⁵=H R³=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R⁴=R⁵=HR⁴=sugar or hydroxy alkyl, amino alkyl/thioalkyl, R²=R³=R⁵=H R⁵=sugar orhydroxy alkyl, amino alkyl/thioalkyl, R²=R³=R⁴=H R²=R⁴=sugar or hydroxyalkyl, amino alkyl/thioalkyl, R³=R⁵=H R³=R⁵=sugar or hydroxy alkyl,amino alkyl/thioalkyl, R²=R⁴=H R²=R⁵=sugar or hydroxy alkyl, aminoalkyl/thioalkyl, R³=R⁴=H R³=R⁴=sugar or hydroxy alkyl, aminoalkyl/thioalkyl, R²=R⁵=H R²=R³=sugar or hydroxy alkyl, aminoalkyl/thioalkyl, R⁴=R⁵=H R⁴=R⁵=sugar or hydroxy alkyl, aminoalkyl/thioalkyl, R²=R³=H Sugars can be monosaccharide pentoses such asD-xylo, D-ribo, D-lyxo, D-ara or the L-sugars such as L-xyl, L-rib,L-lyxo, L-ara in furanoside or pyranoside form; hexoses such as D andL-glc, D and L-gal, D and L-man, D and L-gul, D and L-all, etc. infuranoside/pyranoside form; disaccharides such as lactose, maltose,cellobiose etc.; fully protected as acetates, benzoates, allyl oraralkyl ethers, alkylidene dioxolane derivatives, thio derivatives ortotally unprotected sugars, D and L sugars in furanoside/pyranoside formhaving heterocyclic bases such as adenine, guanine, thymidine, cytosineor unnatural bases or heterocyclics having one or more than oneheteroatoms such as O/N/S both in 5 and 6 membered rings, dexoysugars/amino sugars natural/non-natural, rare sugars and higher sugars,bifunctional sugar amino acids.
 2. Novel C-linked carbo β-peptides classof compounds as claimed in claim 1, wherein compounds having astructural formula shown in here below:


3. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


4. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


5. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


6. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


7. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


8. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


9. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


10. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


11. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


12. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


13. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


14. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


15. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown inherebelow:


16. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


17. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


18. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


19. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


20. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


21. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


22. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


23. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


24. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


25. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


26. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


27. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


28. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


29. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


30. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


31. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


32. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


33. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


34. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


35. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


36. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


37. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


38. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


39. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


40. Novel C-linked carbo β-peptides class of compounds as claimed inclaim 1, wherein compounds having a structural formula shown in herebelow:


41. A method for preparation of novel C-linked carbo β-peptide class ofcompounds having a structure as claimed in claim 1, which have shownstable helical secondary structures: a) reacting C-linked carbo β-aminoacid ester with Pd—C and exposing it to (Boc)₂ to give N-Boc C-linkedcarbo β-amino acid ester b) aqueous alkaline hydrolysis of C-linkedcarbo β-amino acid ester to give the C-linked carbo β-amino acid c) acidmediated hydrolysis of C-linked carbo β-amino acid ester to give thesalt of C-linked amino acid ester d) reacting the C-linked carbo β-aminoacid with amine of C-linked carbo β-amino acid ester under normalpeptide conditions to give dipeptide e) alkaline hydrolysis of dipeptideto give dipeptide acid f) acid hydrolysis of dipeptide to give thedipeptide amine salt g) reacting dipeptide acid with monomer amine saltto give tripeptide h) reacting dipeptide acid with dipeptide salt togive tetrapeptide i) alkaline hydrolysis of tetrapeptide to tetrapeptideacid j) acid hydrolysis of tetrapeptide to tetrapeptide amine salt k)reacting tetrapeptide acid with dipeptide amine salt to give thehexapeptide l) reacting tetrapeptide acid with tetrapeptide amine saltto give the octapeptide
 42. A method of claim 38 wherein the C-linkedcarbo β-amino acid ester is a (S)-epimer or the (R)-epimer at the aminecentre.
 43. A method of claim 38 wherein the alkaline hydrolysis iscarried out on a C-linked carbo β-amino acid ester with (S)-amine centreor C-linked carbo β-amino acid ester with (R)-amine centre
 44. A methodof claim 38 wherein the acid hydrolysis is carried out on C-linked carboβ-amino acid ester with (S) amine centre or C-linked carbo β-amino acidester with (R) amine centre
 45. A method of claim 38 wherein peptidecoupling is carried out on a) with C-linked carbo β-amino acid having(S) amine centre with C-linked carbo β-amino acid ester with (S) aminesalt to give SS dipeptide b) with C-linked carbo β-amino acid having (S)amine centre with C-linked carbo β-amino acid ester with (R) amine saltto give SR dipeptide c) with C-linked carbo β-amino acid having (R)amine centre with C-linked carbo β-amino acid ester with (R) amine saltto give RR dipeptide d) with C-linked carbo β-amino acid having (R)amine centre with C-linked carbo β-amino acid ester with (S) amine saltto give RS dipeptide e) with C-linked carbo β-amino acid having (S)amine with β-Alanine ester having amine salt to give C-linked carboβ-amino acid-β-Alanine mixed dipeptide
 46. A method of claim 38 whereinalkaline hydrolysis is carried out a) SS dipeptide to give SS dipeptideacid b) SR dipeptide to give SR dipeptide acid c) RR dipeptide to giveRR dipeptide acid d) RS dipeptide to give RS dipeptide acid
 47. A methodof claim 38 wherein acid hydrolysis is carried out on a) SS dipeptide togive SS dipeptide salt b) SR dipeptide to give SR dipeptide salt c) RRdipeptide to give RR dipeptide salt d) RS dipeptide to give RS dipeptidesalt
 48. A method of claim 38 wherein peptide coupling is carried out togive tripeptide a) with SS dipeptide acid with C-linked carbo β-aminoacid ester (S) amine salt b) with SR dipeptide acid with C-linked carboβ-amino acid ester (S) amine salt
 49. A method of claim 38 whereinpeptide coupling is carried out to give tetrapeptide a) with SSdipeptide acid and SS dipeptide amine salt to give SSSS tetrapeptide b)with SR dipeptide acid and SR dipeptide amine salt to give SRSRtetrapeptide c) with RR dipeptide acid and RR dipeptide amine salt togive RRRR tetrapeptide d) with RS dipeptide acid and RS dipeptide aminesalt to give RSRS tetrapeptide e) with RS dipeptide acid and SRdipeptide amine salt to give RSSR tetrapeptide f) with SR dipeptide acidand RS dipeptide amine salt to give SRRS tetrapeptide g) with mixeddipeptide acid and mixed dipeptide salt to give mixedS-βAlanine-S-β-alanine tetrapeptide
 50. A method of claim 38 whereinalkaline hydrolysis is carried out on tetrapeptides such as a) SSSStetrapeptide to give SSSS tetrapeptide acid b) SRSR tetrapeptide to giveSRSR tetrapeptide acid c) RRRR tetrapeptide to give RRRR tetrapeptideacid d) RSRS tetrapeptide to give RSRS tetrapeptide acid e)S-β-alanineS-β-alanine mixed tetrapeptide acid
 51. A method of claim 38wherein acid hydrolysis is carried out on tetrapeptides such as a) SSSStetrapeptide to give SSSS tetrapeptide amine salt b) SRSR tetrapeptideto give SRSR tetrapeptide amine salt c) RRRR tetrapeptide to give RRRRtetrapeptide amine salt d) RSRS tetrapeptide to give RSRS tetrapeptideamine salt e) mixed tetrapeptides to give mixed tetrapeptide amine salt52. A method of claim 38 wherein hexapeptides are prepared from a) SStetrapeptide acid and SS dipeptide amine salt to give SSSSSS hexapeptideb) SR tetrapeptide acid and SR dipeptide amine salt to give SRSRSRhexapeptide c) RR tetrapeptide acid and RR dipeptide amine salt to giveRRRRRR hexapeptide d) RS tetrapeptide acid and RS dipeptide amine saltto give RSRSRS hexapeptide e) mixed tetrapeptide acid and mixeddipeptide amine salt to give mixed hexapeptide
 53. A method of claim 38wherein coupling of tetrapeptides are carried out to give octapeptidesuch as a) SSSS tetrapeptide acid and SSSS tetrapeptide amine salt togive octapeptide b) SRSR tetrapeptide acid and SRSR tetrapeptide aminesalt to give octapeptide c) RRRR tetrapeptide acid and RRRR tetrapeptideamine salt to give octapeptide d) RSRS tetrapeptide acid and RSSStetrapeptide amine salt to give octapeptide
 54. A method of claim 1wherein the C-liked carbo β-peptide is represented by the followingformula


55. A method of claim 51 wherein the C-linked carbo-β-peptides hasenvisaged advantage of more solubility than the other β-peptides due tothe carbohydrate moiety
 56. A method of claim 51 wherein the unmaskedcarbohydrate moiety makes the C-linked carbo β-peptides more solublematerials
 57. A method of claim 51 wherein the C-linked carbo β-peptideshave the advantage of hydrophilicity due to the carbohydrate moieties inthe structure
 58. A method of claim 51 wherein the C-linked carboβ-peptides have the advantage of transporting these peptides is easiercompared to other β-peptides due to the carbohydrate moieties in thestructure
 59. A method of claim 51 wherein the C-linked carbo β-peptideswith carbohydrate moieties have the advantage of having carbohydraterecognition on the β-peptides
 60. A method of claim 51 wherein thecarbohydrate moiety on C-linked carbo β-peptides imparts amphiphilicityto the new β-peptides due to hydrophilic nature of carbohydrate moieties61. A method of claim 51 wherein the C-linked carbo β-peptides made fromnonnatural C-linked carbo β-amino acids
 62. A method of claim 51 whereinthe C-linked carbo β-peptides are nonnatural β-peptides
 63. A method ofclaim 51 wherein the nonnatural C-linked carbo β-peptides will haveenhanced stability to peptidases
 64. A method of claim 51 wherein thenonnatural C-linked carbo β-peptides will have enhanced bioavailability65. A method of claim 51 wherein the C-linked carbo β-peptides haveshown stable helical secondary structures
 66. A method of claim 46bwherein the SRSR tetrapeptide has shown an unusal 10/12/10 helicalsecondary structure
 67. A method of claim 49b wherein the SRSRhexapeptide has shown an unuseal10/12/10/12/10 helical secondarystructure
 68. A method of claim 46d wherein the RSRS tetrapeptide hasshown a 12/10 helical secondary structure
 69. A method of claim 49dwherein the RSRS hexapeptide has shown a 12/10/12/10 helical secondarystructure
 70. A method of claim 51 wherein the C-linked carbo β-peptideswith stable secondary structures intercept the activity of normalprotein biopolymer
 71. A method of claim 51 wherein the carbohydratemoieties present on the C-linked carbo β-peptides do not interfere inthe β-peptides conformations
 72. A method of claim 51 wherein theconformational biases imparted by the carbohydrate moiety do not affectthe helical structure portion
 73. A method of claim 51 wherein theC-linked carbo β-peptide having carbohydrate moieties would notinterfere in the carbohydrate recognition
 74. A method of claim 51wherein the C-linked carbo β-peptides with carbohydrate moieties wouldallow the ease transportation of the entire β-peptide moiety
 75. Amethod of claim 51 wherein the C-linked carbo β-peptides withcarbohydrate moieties other than monosaccharides such as di or trisaccharides might improve the solubility due to more hydrophilicity 76.A method of claim 51 wherein the C-linked carbo β-peptides with properlyplaced carbohydrate moieties such as monosaccharides or di saccharidescan induce a high degree of amphiphilicity to the β-peptide moiety
 77. Amethod of claim 51 wherein the C-linked carbo β-peptides with C-linkedcarbo β-amino acid as substituent on the peptide backbone would becamevery interesting compounds pharmacologically.
 78. Novel nonnaturalC-linked carbo-β-peptides with robust secondary structures, claimsubstantially as herein described with reference to the examples anddrawings accompanying this specification.